An observational, retrospective, comprehensive pharmacovigilance analysis of hydroxychloroquine-associated cardiovascular adverse events in patients with and without COVID-19.

BACKGROUND: Coronavirus disease 2019 (COVID-19) is a global pandemic. Hydroxychloroquine (HCQ)-associated cardiovascular adverse events (CVAEs) have been increasingly reported. AIM: This study aimed to present an observational, retrospective, and comprehensive pharmacovigilance analysis of CVAE associated with HCQ in patients with and without COVID-19 using the US Food and Drug Administration Adverse Events Reporting System (FAERS) data from January 2020 to December 2020. METHOD: We identified 3302 adverse event reports from the FAERS database in the year 2020 and divided them into COVID-19 and non-COVID-19 groups, respectively. Then we analyzed whether there were differences in CVAEs between the two groups. RESULTS: We found that CVAE was higher in cases with COVID-19 compared to those without COVID-19, odds ratio (OR) of 1.26 and a 95% confidence interval (95% CI) of 1.02-1.54. Cases with COVID-19 treated with HCQ exhibited relatively higher proportions of torsade de points (TdP) and QT prolongation (OR 3.10, 95% CI 2.24-4.30), shock-associated TdP (OR 2.93, 95% CI 2.13-4.04), cardiac arrhythmias (OR 2.07, 95% CI 1.60-2.69), cardiac arrhythmia terms (including bradyarrhythmias and tachyarrhythmias) (OR 2.15, 95% CI 1.65-2.80), bradyarrhythmias (including conduction defects and disorders of sinus node function) (OR 2.56, 95% CI 1.86-3.54), and conduction defects (OR 2.56, 95% CI 1.86-3.54). CONCLUSION: Our retrospective observational analysis suggested that the proportion of CVAE associated with HCQ, especially TdP and QT prolongation, was higher in patients with COVID-19. Understanding the effects of COVID-19 on the cardiovascular system is essential to providing comprehensive medical care to patients receiving HCQ treatment.

Revisiting QT prolongation in acute rheumatic fever - Relevance for hydroxychloroquine treatment.

In-vitro evidence suggests hydroxychloroquine could be a potential immunomodulator for the inflammatory carditis of acute rheumatic fever (ARF). Hydroxychloroquine used as an anti-inflammatory agent has a low side effect profile but its use in the Covid-19 pandemic raised concerns about QTc interval prolongation and cardiac arrhythmias. The prolongation of QTc in ARF appears benign but has not been widely studied. We aim to report QTc intervals in a contemporary ARF population and consider implications for hydroxychloroquine use in ARF. The study cohort was 197 children <15 years of age with a clinical diagnosis of ARF. The QTc mean (SD) was 445 msec (28), range 370-545 msec. Eighteen percent of the cohort had a QTc > 99th percentile for normal by age and 8 patients (4%) had a QTc over 500 msec. There was no difference of QTc by age or gender. Inter-observer repeatability for QTc (n = 33) was 35 msec. The QTc is often prolonged in the early phase of ARF, meaning that QT prolonging medications should be used with caution in this setting. Serial ECG monitoring of the QT interval is recommended if hydroxycholoroquine is used in ARF.

Safety profile of hydroxychloroquine used off-label for the treatment of patients with COVID-19: A descriptive study based on EudraVigilance data.

At the beginning of the COVID-19 pandemic, worldwide attempts were made to identify potential drugs effective against the COVID-19. Hydroxychloroquine was among the first receiving attention. However, following its use in therapy, it has been shown that hydroxychloroquine was not only ineffective but probably, due to its known side effects, even responsible of increased mortality of patients. The objective of this study was to review the safety profile of hydroxychloroquine used off-label for the treatment of COVID-19. We analyze the reports of suspected adverse drug reactions (ADRs) collected in EudraVigilance, the European database of ADR reports. We collected 2266 reports for 2019 and 6525 for 2020. The most reported ADRs during 2020 were those relating to cardiac, hepatic, renal toxicity such as QT prolongation with 400 cases in 2020 (of which, 345 cases-9.97%-with COVID-19 as a therapeutic indication) versus 1 case only in 2019 (0.01%), long QT syndrome: 38 cases in 2020 (36 as COVID-19 treatment) versus 0 in 2019, hepatitis: 13 cases in 2019 (0.11%) and 132 in 2020, and 32 cases (24, 0.69%) of acute kidney injury in 2020 and only 3 cases in 2019. Moreover, some important vision-related ADRs also increased significantly during 2020, such as retinal toxicity with 92 cases in 2020 versus 7 in 2019. Even though with its intrinsic limitations, our results may be added to the most recent scientific evidence to confirm the unfavorable risk profile of hydroxychloroquine in its off-label use in the treatment of COVID-19 disease.

Hydroxychloroquine cardiotoxicity: a case-control study comparing patients with COVID-19 and patients with systemic lupus erythematosus.

OBJECTIVES: Antimalarials have been associated with QT prolongation in COVID-19 patients but are generally safe in systemic lupus erythematosus (SLE).We compared the prevalence of QTc prolongation between COVID-19 and SLE patients treated with hydroxychloroquine (HCQ). METHODS: We included patients with SARS-CoV-2 infection confirmed by nasopharyngeal swab and patients taking HCQ for SLE. A prolonged QTc was defined as an increase in QTc intervals >60 ms (compared with baseline) or as a QTc of ≥500 ms. We performed the univariate and multivariate logistic regression to investigate the risk factors for QTc prolongation in COVID-19 patients. RESULTS: We enrolled 58 COVID-19 patients (median age 70.5 years, IQR 25), grouped into group A (patients with HCQ) group B (patients with HCQ + azithromycin) and group C (not received either drug). Fifty (26%) COVID-19 patients presented a QTc prolongation (12 QTc≥500 ms, 3 patients ΔQTc>60 ms). We did not find any differences in QTc prolongation among the three treatment groups. Baseline QTc (OR 111.5) and D-dimer (OR 78.3) were independently associated to QTc prolongation. Compared to the 50 SLE patients (median age 38.5 years, IQR 22), chronically treated with HCQ, COVID-19 patients showed significantly longer QTc (p<0.001). CONCLUSIONS: This is the first study demonstrating that, unlike COVID-19 patients, patients with SLE are not susceptible to HCQ-induced long QT syndrome and arrhythmia. The combined arrhythmogenic effect of SARS-CoV-2 infection and HCQ could account for the excess of QTc prolongation and fatal arrhythmias described in patients with COVID-19.

Comparative study of the adverse event profile of hydroxychloroquine before and during the Sars-CoV2 pandemic.

AIMS: At the beginning of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pandemic, there were no clinically-tested medications for the effective treatment of coronavirus disease. In this context, on 5 March 2020, the French Public Health Council issued several recommendations for the therapeutic management of this new disease, including the use of hydroxychloroquine (HCQ). An unexpected cardiovascular safety signal was quickly identified as being more frequent than expected thanks to the reports of adverse drug reactions (ADRs) submitted to French regional pharmacovigilance centres (RPVC). The objective of this study was to compare all ADRs reported with HCQ used in its usual indication, collected before the pandemic period (1985 to 31 December, 2019) with those reported with the coronavirus disease 2019 (COVID-19) indication (1 January to 21 July, 2020). METHODS: For this purpose, reports were extracted from the French pharmacovigilance database and analysed for these two periods. RESULTS: Our study showed a different safety profile in COVID-19 patients with more cardiac disorders (57% of ADRs versus 5% before the pandemic period), especially QT interval prolongation, resulting from an interaction with azithromycin in more than 20% of cases. Hepatobiliary disorders were also significantly more frequent. CONCLUSIONS: These observations could be associated with the effect of the virus itself on the various organs, the profile of the patients treated, and concomitant drug treatments.

Drug-Induced QTc Prolongation: What We Know and Where We Are Going.

Drug-induced QTc prolongation is a concerning electrocardiogram (ECG) abnormality. This cardiac disturbance carries a 10% risk of sudden cardiac death due to the malignant arrhythmia, Torsades de Pointes. The Arizona Center for Education and Research on Therapeutics (AzCERT) has classified QTc prolonging therapeutic classes, such as antiarrhythmics, antipsychotics, anti-infectives, and others. AzCERT criteria categorize medications into three risk categories: "known," "possible," and "conditional risk" of QTc prolongation and Torsades de Pointes. The list of QTc prolonging medications continues to expand as new drug classes are approved and studied. Risk factors for QTc prolongation can be delineated into modifiable or non-modifiable. A validated risk scoring tool may be utilized to predict the likelihood of prolongation in patients receiving AzCERT classified medication. The resultant risk score may be applied to a clinical decision support system, which offers mitigation strategies. Mitigation strategies including discontinuation of possible offending agents with a selection of an alternative agent, assessment of potential drug interactions or dose adjustments through pharmacokinetic and pharmacodynamic monitoring, and initiation of both ECG and electrolyte monitoring are essential to prevent a drug-induced arrhythmia. The challenges presented by the COVID-19 pandemic have led to the development of innovative continuous monitoring technology, increasing protection for both patients and healthcare workers. Early intervention strategies may reduce adverse events and improve clinical outcomes in patients identified to be at risk of QTc prolongation.

Hydroxychloroquine and Azithromycin Combination in the Management of COVID-19 Infection: Safety and Effectiveness Challenges.

BACKGROUND: The treatment of COVID-19 disease remains a dilemma so far because there is no approved therapy for it. This study aimed to evaluate the use of hydroxychloroquine and azithromycin combination in treatment. OBJECTIVES: This study was carried out to determine the safety and effectiveness of hydroxychloroquine and azithromycin combination in COVID 19 patients. METHODS: This study included 90 adult COVID 19 patients. Treatment of all patients followed Egyptian Ministry of Health COVID-19 protocols, receiving a combination of hydroxychloroquine 400mg twice on day 1, then 200 mg twice daily in addition to azithromycin 500mg/day for 5 days. ECG findings, especially the QTc interval, were assessed before and after 5 days from the administration. RESULTS: All patients showed a statistically significant higher post-treatment QTc readings (433.6 ± 37.2) compared to baseline QTc (402.4 ± 31.3) at p<0.005 with a median QTc prolongation by 26 mSec and IQR (17.8-41.3), but without serious clinical complications. Only 5.6% of patients showed QTc more than 500 mSec and no torsade de points or cardiac arrest. Geriatric patients were at higher risk for QTc prolongation compared to patients aged less than 65 years but without a significant difference as regards the median max QTc difference p˂0.65. The expected therapeutic effectiveness was 82.5% for moderate patients compared to 26% for severe patients (P<0.005). CONCLUSION: In a modest safety profile, we support the evidence that HQ/AZ therapy can be used to treat Covid-19 infection with more effectiveness in moderate rather than severe cases, which might be a reflection of the time of administration in the disease course.

Validating and implementing cardiac telemetry for continuous QTc monitoring: A novel approach to increase healthcare personnel safety during the COVID-19 pandemic.

BACKGROUND: Minimizing direct patient contact among healthcare personnel is crucial for mitigating infectious risk during the coronavirus disease 2019 (COVID-19) pandemic. The use of remote cardiac telemetry as an alternative to 12­lead electrocardiography (ECG) for continuous QTc monitoring may facilitate this strategy, but its application has not yet been validated or implemented. METHODS: In the validation component of this two-part prospective cohort study, a total of 65 hospitalized patients with simultaneous ECG and telemetry were identified. QTc obtained via remote telemetry as measured by 3 independent, blinded operators were compared with ECG as assessed by 2 board-certified electrophysiologists as the gold-standard. Pearson correlation coefficients were calculated to measure the strength of linear correlation between the two methods. In a separate cohort comprised of 68 COVID-19 patients treated with combined hydroxychloroquine and azithromycin, telemetry-based QTc values were compared at serial time points after medication administration using Friedman rank-sum test of repeated measures. RESULTS: Telemetry-based QTc measurements highly correlated with QTc values derived from ECG, with correlation coefficients of 0.74, 0.79, 0.85 (individual operators), and 0.84 (mean of all operators). Among the COVID-19 cohort, treatment led to a median QTc increase of 15 milliseconds between baseline and following the 9th dose (p = 0.002), with 8 (12%) patients exhibiting an increase in QTc ≥ 60 milliseconds and 4 (6%) developing QTc ≥ 500 milliseconds. CONCLUSIONS: Cardiac telemetry is a validated clinical tool for QTc monitoring that may serve an expanding role during the COVID-19 pandemic strengthened by its remote and continuous monitoring capability and ubiquitous presence throughout hospitals.

Cardiac Corrected QT Interval Changes Among Patients Treated for COVID-19 Infection During the Early Phase of the Pandemic.

Importance: Critical illness, a marked inflammatory response, and viruses such as SARS-CoV-2 may prolong corrected QT interval (QTc). Objective: To evaluate baseline QTc interval on 12-lead electrocardiograms (ECGs) and ensuing changes among patients with and without COVID-19. Design, Setting, and Participants: This cohort study included 3050 patients aged 18 years and older who underwent SARS-CoV-2 testing and had ECGs at Columbia University Irving Medical Center from March 1 through May 1, 2020. Patients were analyzed by treatment group over 5 days, as follows: hydroxychloroquine with azithromycin, hydroxychloroquine alone, azithromycin alone, and neither hydroxychloroquine nor azithromycin. ECGs were manually analyzed by electrophysiologists masked to COVID-19 status. Multivariable modeling evaluated clinical associations with QTc prolongation from baseline. Exposures: COVID-19, hydroxychloroquine, azithromycin. Main Outcomes and Measures: Mean QTc prolongation, percentage of patients with QTc of 500 milliseconds or greater. Results: A total of 965 patients had more than 2 ECGs and were included in the study, with 561 (58.1%) men, 198 (26.2%) Black patients, and 191 (19.8%) aged 80 years and older. There were 733 patients (76.0%) with COVID-19 and 232 patients (24.0%) without COVID-19. COVID-19 infection was associated with significant mean QTc prolongation from baseline by both 5-day and 2-day multivariable models (5-day, patients with COVID-19: 20.81 [95% CI, 15.29 to 26.33] milliseconds; P < .001; patients without COVID-19: -2.01 [95% CI, -17.31 to 21.32] milliseconds; P = .93; 2-day, patients with COVID-19: 17.40 [95% CI, 12.65 to 22.16] milliseconds; P < .001; patients without COVID-19: 0.11 [95% CI, -12.60 to 12.81] milliseconds; P = .99). COVID-19 infection was independently associated with a modeled mean 27.32 (95% CI, 4.63-43.21) millisecond increase in QTc at 5 days compared with COVID-19-negative status (mean QTc, with COVID-19: 450.45 [95% CI, 441.6 to 459.3] milliseconds; without COVID-19: 423.13 [95% CI, 403.25 to 443.01] milliseconds; P = .01). More patients with COVID-19 not receiving hydroxychloroquine and azithromycin had QTc of 500 milliseconds or greater compared with patients without COVID-19 (34 of 136 [25.0%] vs 17 of 158 [10.8%], P = .002). Multivariable analysis revealed that age 80 years and older compared with those younger than 50 years (mean difference in QTc, 11.91 [SE, 4.69; 95% CI, 2.73 to 21.09]; P = .01), severe chronic kidney disease compared with no chronic kidney disease (mean difference in QTc, 12.20 [SE, 5.26; 95% CI, 1.89 to 22.51; P = .02]), elevated high-sensitivity troponin levels (mean difference in QTc, 5.05 [SE, 1.19; 95% CI, 2.72 to 7.38]; P < .001), and elevated lactate dehydrogenase levels (mean difference in QTc, 5.31 [SE, 2.68; 95% CI, 0.06 to 10.57]; P = .04) were associated with QTc prolongation. Torsades de pointes occurred in 1 patient (0.1%) with COVID-19. Conclusions and Relevance: In this cohort study, COVID-19 infection was independently associated with significant mean QTc prolongation at days 5 and 2 of hospitalization compared with day 0. More patients with COVID-19 had QTc of 500 milliseconds or greater compared with patients without COVID-19.

Adverse drug event risk assessment by the virtual addition of COVID-19 repurposed drugs to Medicare and commercially insured patients' drug regimens: A drug safety simulation study.

Drug safety is generally established from clinical trials, by pharmacovigilance programs and during observational phase IV safety studies according to drug intended or approved indications. The objective of this study was to estimate the risk of potential adverse drug events (ADEs) associated with drugs repurposed for coronavirus disease 2019 (COVID-19) treatment in a large-scale population. Drug claims were used to calculate a baseline medication risk score (MRS) indicative of ADE risk level. Fictitious claims of repurposed drugs were added, one at a time, to patients' drug regimens to calculate a new MRS and compute a level of risk. Drug claims data from enrollees with Regence health insurance were used and sub-payer analyses were performed with Medicare and commercial insured groups. Simulated interventions were conducted with hydroxychloroquine and chloroquine, alone or combined with azithromycin, and lopinavir/ritonavir, along with terfenadine and fexofenadine as positive and negative controls for drug-induced Long QT Syndrome (LQTS). There were 527,471 subjects (56.6% women; mean [SD] age, 47 years [21]) were studied. The simulated addition of each repurposed drug caused an increased risk of ADEs (median MRS increased by two-to-seven points, p < 0.001). The increase in ADE risk was mainly driven by an increase in CYP450 drug interaction risk score and by drug-induced LQTS risk score. The Medicare group presented a greater risk overall compared to the commercial group. All repurposed drugs were associated with an increased risk of ADEs. Our simulation strategy could be used as a blueprint to preemptively assess safety associated with future repurposed or new drugs.

Coronavirus disease 2019 (COVID-19) and QTc prolongation.

INTRODUCTION: The cause-and-effect relationship of QTc prolongation in Coronavirus disease 2019 (COVID-19) patients has not been studied well. OBJECTIVE: We attempt to better understand the relationship of QTc prolongation in COVID-19 patients in this study. METHODS: This is a retrospective, hospital-based, observational study. All patients with normal baseline QTc interval who were hospitalized with the diagnosis of COVID-19 infection at two hospitals in Ohio, USA were included in this study. RESULTS: Sixty-nine patients had QTc prolongation, and 210 patients continued to have normal QTc during hospitalization. The baseline QTc intervals were comparable in the two groups. Patients with QTc prolongation were older (mean age 67 vs. 60, P 0.003), more likely to have underlying cardiovascular disease (48% versus 26%, P 0.001), ischemic heart disease (29% versus 17%, P 0.026), congestive heart failure with preserved ejection fraction (16% versus 8%, P 0.042), chronic kidney disease (23% versus 10%, P 0.005), and end-stage renal disease (12% versus 1%, P < 0.001). Patients with QTc prolongation were more likely to have received hydroxychloroquine (75% versus 59%, P 0.018), azithromycin (18% vs. 14%, P 0.034), a combination of hydroxychloroquine and azithromycin (29% vs 7%, P < 0.001), more than 1 QT prolonging agents (59% vs. 32%, P < 0.001). Patients who were on angiotensin-converting enzyme inhibitors (ACEi) were less likely to develop QTc prolongation (11% versus 26%, P 0.014). QTc prolongation was not associated with increased ventricular arrhythmias or mortality. CONCLUSION: Older age, ESRD, underlying cardiovascular disease, potential virus mediated cardiac injury, and drugs like hydroxychloroquine/azithromycin, contribute to QTc prolongation in COVID-19 patients. The role of ACEi in preventing QTc prolongation in COVID-19 patients needs to be studied further.

Off-label use of chloroquine, hydroxychloroquine, azithromycin and lopinavir/ritonavir in COVID-19 risks prolonging the QT interval by targeting the hERG channel.

Coronavirus disease-2019 (COVID-19), caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), poses an enormous challenge to the medical system, especially the lack of safe and effective COVID-19 treatment methods, forcing people to look for drugs that may have therapeutic effects as soon as possible. Some old drugs have shown clinical benefits after a few small clinical trials that attracted great attention. Clinically, however, many drugs, including those currently used in COVID-19, such as chloroquine, hydroxychloroquine, azithromycin, and lopinavir/ritonavir, may cause cardiotoxicity by acting on cardiac potassium channels, especially hERG channel through their off-target effects. The blocking of the hERG channel prolongs QT intervals on electrocardiograms; thus, it might induce severe ventricular arrhythmias and even sudden cardiac death. Therefore, while focusing on the efficacy of COVID-19 drugs, the fact that they block hERG channels to cause arrhythmias cannot be ignored. To develop safer and more effective drugs, it is necessary to understand the interactions between drugs and the hERG channel and the molecular mechanism behind this high affinity. In this review, we focus on the biochemical and molecular mechanistic aspects of drug-related blockade of the hERG channel to provide insights into QT prolongation caused by off-label use of related drugs in COVID-19, and hope to weigh the risks and benefits when using these drugs.

COVID-19 FAQs in paediatric and congenital cardiology: AEPC position paper.

The COVID-19 pandemic has had a huge influence in almost all areas of life, affecting societies, economics, and health care systems worldwide. The paediatric cardiology community is no exception. As the challenging battle with COVID-19 continues, professionals from the Association for the European Paediatric and Congenital Cardiology receive many questions regarding COVID-19 in a Paediatric and Congenital Cardiology setting. The aim of this paper is to present the AEPC position on frequently asked questions based on the most recent scientific data, as well as to frame a discussion on how to take care of our patients during this unprecedented crisis. As the times are changing quickly and information regarding COVID-19 is very dynamic, continuous collection of evidence will help guide constructive decision-making.

Sex Differences in Reported Adverse Drug Reactions to COVID-19 Drugs in a Global Database of Individual Case Safety Reports.

INTRODUCTION: In late 2019, a new coronavirus-severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)-was discovered in Wuhan, China, and the World Health Organization later declared coronavirus disease 2019 (COVID-19) a pandemic. Numerous drugs have been repurposed and investigated for therapeutic effectiveness in the disease, including those from "Solidarity," an international clinical trial (azithromycin, chloroquine, hydroxychloroquine, the fixed combination lopinavir/ritonavir, and remdesivir). OBJECTIVE: Our objective was to evaluate adverse drug reaction (ADR) reporting for drugs when used in the treatment of COVID-19 compared with use for other indications, specifically focussing on sex differences. METHOD: We extracted reports on COVID-19-specific treatments from the global ADR database, VigiBase, using an algorithm developed to identify reports that listed COVID-19 as the indication. The Solidarity trial drugs were included, as were any drugs reported ≥ 100 times. We performed a descriptive comparison of reports for the same drugs used in non-COVID-19 indications. The data lock point date was 7 June 2020. RESULTS: In total, 2573 reports were identified for drugs used in the treatment of COVID-19. In order of frequency, the most reported ADRs were electrocardiogram QT-prolonged, diarrhoea, nausea, hepatitis, and vomiting in males and diarrhoea, electrocardiogram QT-prolonged, nausea, vomiting, and upper abdominal pain in females. Other hepatic and kidney-related events were included in the top ten ADRs in males, whereas no hepatic or renal terms were reported for females. COVID-19-related reporting patterns differed from non-pandemic reporting for these drugs. CONCLUSION: Review of a global database of suspected ADR reports revealed sex differences in the reporting patterns for drugs used in the treatment of COVID-19. Patterns of ADR sex differences need further elucidation.

Spontaneous reported cardiotoxicity induced by lopinavir/ritonavir in COVID-19. An alleged past-resolved problem.

The antiretroviral drug lopinavir/ritonavir has been recently repurposed for the treatment of COVID-19. Its empirical use has been associated with multiple cardiac adverse reactions pertaining to its ancillary multi-channel blocking properties, vaguely characterized until now. We aimed to characterize qualitatively the cardiotoxicity associated with lopinavir/ritonavir in the setting of COVID-19. Spontaneous notifications of cardiac adverse drug reactions reported to the national Pharmacovigilance Network were collected for 8 weeks since March 1st 2020. The Nice Regional Center of Pharmacovigilance, whose scope of expertise is drug-induced long QT syndrome, analyzed the cases, including the reassessment of all available ECGs. QTc ≥ 500 ms and delta QTc > 60 ms from baseline were deemed serious. Twenty-two cases presented with 28 cardiac adverse reactions associated with the empirical use of lopinavir/ritonavir in a hospital setting. Most adverse reactions reflected lopinavir/ritonavir potency to block voltage-gated potassium channels with 5 ventricular arrhythmias and 17 QTc prolongations. An average QTc augmentation of 97 ± 69 ms was reported. Twelve QTc prolongations were deemed serious. Other cases were likely related to lopinavir/ritonavir potency to block sodium channels: 1 case of bundle branch block and 5 recurrent bradycardias. The incidence of cardiac adverse reactions of lopinavir/ritonavir was estimated between 0.3% and 0.4%. These cardiac adverse drug reactions offer a new insight in its ancillary multi-channel blocking functions. Lopinavir/ritonavir cardiotoxicity may be of concern for its empirical use during the COVID-19 pandemic. Caution should be exerted relative to this risk where lopinavir/ritonavir summary of product characteristics should be implemented accordingly.

Smartwatch Electrocardiogram and Artificial Intelligence for Assessing Cardiac-Rhythm Safety of Drug Therapy in the COVID-19 Pandemic. The QT-logs study.

BACKGROUND: QTc interval monitoring, for the prevention of drug-induced arrhythmias is necessary, especially in the context of coronavirus disease 2019 (COVID-19). For the provision of widespread use, surrogates for 12­lead ECG QTc assessment may be useful. This prospective observational study compared QTc duration assessed by artificial intelligence (AI-QTc) (Cardiologs®, Paris, France) on smartwatch single­lead electrocardiograms (SW-ECGs) with those measured on 12­lead ECGs, in patients with early stage COVID-19 treated with a hydroxychloroquine-azithromycin regimen. METHODS: Consecutive patients with COVID-19 who needed hydroxychloroquine-azithromycin therapy, received a smartwatch (Withings Move ECG®, Withings, France). At baseline, day-6 and day-10, a 12­lead ECG was recorded, and a SW-ECG was transmitted thereafter. Throughout the drug regimen, a SW-ECG was transmitted every morning at rest. Agreement between manual QTc measurement on a 12­lead ECG and AI-QTc on the corresponding SW-ECG was assessed by the Bland-Altman method. RESULTS: 85 patients (30 men, mean age 38.3 ± 12.2 years) were included in the study. Fair agreement between manual and AI-QTc values was observed, particularly at day-10, where the delay between the 12­lead ECG and the SW-ECG was the shortest (-2.6 ± 64.7 min): 407 ± 26 ms on the 12­lead ECG vs 407 ± 22 ms on SW-ECG, bias -1 ms, limits of agreement -46 ms to +45 ms; the difference between the two measures was <50 ms in 98.2% of patients. CONCLUSION: In real-world epidemic conditions, AI-QTc duration measured by SW-ECG is in fair agreement with manual measurements on 12­lead ECGs. Following further validation, AI-assisted SW-ECGs may be suitable for QTc interval monitoring. REGISTRATION: ClinicalTrial.govNCT04371744.

Hydroxychloroquine/Azithromycin Therapy and QT Prolongation in Hospitalized Patients With COVID-19.

OBJECTIVES: This study aimed to characterize corrected QT (QTc) prolongation in a cohort of hospitalized patients with coronavirus disease-2019 (COVID-19) who were treated with hydroxychloroquine and azithromycin (HCQ/AZM). BACKGROUND: HCQ/AZM is being widely used to treat COVID-19 despite the known risk of QT interval prolongation and the unknown risk of arrhythmogenesis in this population. METHODS: A retrospective cohort of COVID-19 hospitalized patients treated with HCQ/AZM was reviewed. The QTc interval was calculated before drug administration and for the first 5 days following initiation. The primary endpoint was the magnitude of QTc prolongation, and factors associated with QTc prolongation. Secondary endpoints were incidences of sustained ventricular tachycardia or ventricular fibrillation and all-cause mortality. RESULTS: Among 415 patients who received concomitant HCQ/AZM, the mean QTc increased from 443 ± 25 ms to a maximum of 473 ± 40 ms (87 [21%] patients had a QTc ≥500 ms). Factors associated with QTc prolongation ≥500 ms were age (p < 0.001), body mass index <30 kg/m2 (p = 0.005), heart failure (p < 0.001), elevated creatinine (p = 0.005), and peak troponin (p < 0.001). The change in QTc was not associated with death over the short period of the study in a population in which mortality was already high (hazard ratio: 0.998; p = 0.607). No primary high-grade ventricular arrhythmias were observed. CONCLUSIONS: An increase in QTc was seen in hospitalized patients with COVID-19 treated with HCQ/AZM. Several clinical factors were associated with greater QTc prolongation. Changes in QTc were not associated with increased risk of death.

Hydroxychloroquine/azithromycin treatment, QT interval and ventricular arrhythmias in hospitalised patients with COVID-19.

BACKGROUND: Hydroxychloroquine (HCQ) and azithromycin (AZM) are widely used in off-label treatment of novel coronavirus disease (COVID-19). However, cardiac safety of these drugs is still controversial in COVID-19. Therefore, we aimed to evaluate association of HCQ or HCQ + AZM treatment regimens, corrected QT (QTc) interval and malignant ventricular arrhythmias in hospitalized patients. METHODS: This is a single-center, retrospective and observational study. All data were extracted from the electronic medical records. The initial and post-treatment mean QTc intervals were calculated and compared in patients with HCQ alone or HCQ + AZM therapy. Associated factors with QTc prolongation, the incidence of ventricular arrhythmia during treatment and in-hospital mortality because of ventricular arrhythmias were evaluated. RESULTS: Our cohort comprised 101 hospitalized COVID-19 patients (mean age of 49.60 ± 18 years, 54.4% men). HCQ + AZM combination therapy group (n = 56) was more likely to have comorbidities. After 5-days treatment, 19 (18.8%) patients had QTc prolongation, and significant increase in the QTc interval was observed in both two groups (P < .001). However, HCQ + AZM combination group had significantly higher ΔQTc compared to HCQ group (22.5 ± 18.4 vs 7.5 ± 15.3 ms, P < .001). All of 101 patients completed the 5-days treatment without interruption. Also, no malignant ventricular arrhythmia or death secondary to ventricular arrhythmia occurred during the treatment in both groups. CONCLUSIONS: The present study revealed that although HCQ + AZM treatment was independently associated with QTc prolongation, none of patients experienced malignant ventricular arrhythmia or death during treatment. Further prospective studies are needed to determine the exact implications of these drugs on arrhythmias in patients with COVID-19.

QTc Prolongation in COVID-19 Patients Using Chloroquine.

Chloroquine is used in the treatment of patients with COVID-19 infection, although there is no substantial evidence for a beneficial effect. Chloroquine is known to prolong the QRS and QTc interval on the ECG. To assess the effect of chloroquine on QRS and QTc intervals in COVID-19 patients, we included all inpatients treated with chloroquine for COVID-19 in the Spaarne Gasthuis (Haarlem/Hoofddorp, the Netherlands) and had an ECG performed both in the 72 h before and during or at least 48 h after treatment. We analyzed the (change in) QRS and QTc interval using the one-sample t-test. Of the 106 patients treated with chloroquine, 70 met the inclusion criteria. The average change in QRS interval was 6.0 ms (95% CI 3.3-8.7) and the average change in QTc interval was 32.6 ms (95% CI 24.9-40.2) corrected with the Bazett's formula and 38.1 ms (95% CI 30.4-45.9) corrected with the Fridericia's formula. In 19 of the 70 patients (27%), the QTc interval was above 500 ms after start of chloroquine treatment or the change in QTc interval was more than 60 ms. A heart rate above 90 bpm, renal dysfunction, and a QTc interval below 450 ms were risk factors for QTc interval prolongation. Chloroquine prolongs the QTc interval in a substantial number of patients, potentially causing rhythm disturbances. Since there is no substantial evidence for a beneficial effect of chloroquine, these results discourage its use in COVID-19 patients.