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1.
J Electrocardiol ; 67: 1-6, 2021.
Article in English | MEDLINE | ID: covidwho-1222930

ABSTRACT

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.


Subject(s)
COVID-19 , Long QT Syndrome , Delivery of Health Care , Electrocardiography , Humans , Long QT Syndrome/diagnosis , Long QT Syndrome/epidemiology , Pandemics , Prospective Studies , SARS-CoV-2 , Telemetry
2.
JAMA Netw Open ; 4(4): e216842, 2021 04 01.
Article in English | MEDLINE | ID: covidwho-1198342

ABSTRACT

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.


Subject(s)
Azithromycin , COVID-19 , Electrocardiography , Hydroxychloroquine , Long QT Syndrome , Aged, 80 and over , Anti-Infective Agents/administration & dosage , Anti-Infective Agents/adverse effects , Azithromycin/administration & dosage , Azithromycin/adverse effects , COVID-19/diagnosis , COVID-19/drug therapy , COVID-19/epidemiology , COVID-19 Testing/methods , Drug Therapy, Combination/methods , Drug Therapy, Combination/statistics & numerical data , Electrocardiography/methods , Electrocardiography/statistics & numerical data , Female , Hospitalization/statistics & numerical data , Humans , Hydroxychloroquine/administration & dosage , Hydroxychloroquine/adverse effects , Long QT Syndrome/chemically induced , Long QT Syndrome/diagnosis , Long QT Syndrome/epidemiology , Long QT Syndrome/virology , Male , Middle Aged , New York/epidemiology , Outcome and Process Assessment, Health Care , Risk Factors , SARS-CoV-2 , Time Factors
3.
Clin Transl Sci ; 14(5): 1799-1809, 2021 09.
Article in English | MEDLINE | ID: covidwho-1160763

ABSTRACT

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.


Subject(s)
Antiviral Agents/adverse effects , COVID-19/drug therapy , Drug Repositioning , Long QT Syndrome/epidemiology , Administrative Claims, Healthcare/statistics & numerical data , Adolescent , Adult , Aged , Aged, 80 and over , Antiviral Agents/administration & dosage , Antiviral Agents/pharmacokinetics , COVID-19/complications , COVID-19/virology , Child , Child, Preschool , Computer Simulation , Cytochrome P-450 Enzyme System/metabolism , Drug Interactions , Female , Humans , Infant , Infant, Newborn , Long QT Syndrome/chemically induced , Male , Medicare/statistics & numerical data , Middle Aged , Pharmacovigilance , Retrospective Studies , Risk Assessment/methods , Risk Assessment/statistics & numerical data , United States/epidemiology , Young Adult
4.
BMC Cardiovasc Disord ; 21(1): 158, 2021 03 30.
Article in English | MEDLINE | ID: covidwho-1159221

ABSTRACT

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.


Subject(s)
COVID-19/drug therapy , Cardiovascular Diseases/epidemiology , Electrocardiography , Long QT Syndrome , Renal Insufficiency, Chronic/epidemiology , Age Factors , Aged , COVID-19/classification , COVID-19/complications , COVID-19/epidemiology , COVID-19/physiopathology , COVID-19/therapy , Comorbidity , Correlation of Data , Electrocardiography/methods , Electrocardiography/statistics & numerical data , Female , Humans , Long QT Syndrome/diagnosis , Long QT Syndrome/epidemiology , Long QT Syndrome/etiology , Male , Middle Aged , Outcome and Process Assessment, Health Care , Risk Assessment/methods , SARS-CoV-2/isolation & purification , Survival Analysis , United States/epidemiology
5.
Eur J Pharmacol ; 893: 173813, 2021 Feb 15.
Article in English | MEDLINE | ID: covidwho-1116627

ABSTRACT

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.


Subject(s)
Azithromycin/adverse effects , Azithromycin/therapeutic use , COVID-19/complications , COVID-19/drug therapy , Chloroquine/adverse effects , Chloroquine/therapeutic use , ERG1 Potassium Channel/drug effects , Hydroxychloroquine/adverse effects , Hydroxychloroquine/therapeutic use , Long QT Syndrome/chemically induced , Lopinavir/adverse effects , Lopinavir/therapeutic use , Ritonavir/adverse effects , Ritonavir/therapeutic use , Drug Combinations , Humans , Long QT Syndrome/epidemiology , Off-Label Use
6.
Cardiol Young ; 31(3): 344-351, 2021 Mar.
Article in English | MEDLINE | ID: covidwho-1101608

ABSTRACT

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.


Subject(s)
Anti-Arrhythmia Agents/therapeutic use , Anticoagulants/therapeutic use , Antiviral Agents/therapeutic use , Arrhythmias, Cardiac/drug therapy , COVID-19/drug therapy , Heart Defects, Congenital/therapy , Immunologic Factors/therapeutic use , Adenosine Monophosphate/analogs & derivatives , Adenosine Monophosphate/therapeutic use , Alanine/analogs & derivatives , Alanine/therapeutic use , Arrhythmias, Cardiac/epidemiology , Arrhythmias, Cardiac/physiopathology , Brugada Syndrome/drug therapy , Brugada Syndrome/epidemiology , Brugada Syndrome/physiopathology , COVID-19/epidemiology , COVID-19/physiopathology , Cardiac Surgical Procedures , Cardiology , Heart Defects, Congenital/epidemiology , Heart Defects, Congenital/physiopathology , Heart Transplantation , Humans , Infectious Disease Transmission, Vertical , Long QT Syndrome/drug therapy , Long QT Syndrome/epidemiology , Long QT Syndrome/physiopathology , Myocarditis/epidemiology , Myocarditis/physiopathology , Myocardium , Pediatrics , Risk Assessment , SARS-CoV-2 , Societies, Medical , Systemic Inflammatory Response Syndrome/drug therapy , Systemic Inflammatory Response Syndrome/epidemiology , Systemic Inflammatory Response Syndrome/physiopathology , Tachycardia, Ventricular/drug therapy , Tachycardia, Ventricular/epidemiology , Tachycardia, Ventricular/physiopathology
7.
Drug Saf ; 43(12): 1309-1314, 2020 12.
Article in English | MEDLINE | ID: covidwho-1092869

ABSTRACT

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.


Subject(s)
Antiviral Agents/adverse effects , COVID-19/drug therapy , Drug-Related Side Effects and Adverse Reactions/epidemiology , Abdominal Pain/chemically induced , Abdominal Pain/epidemiology , Adenosine Monophosphate/adverse effects , Adenosine Monophosphate/analogs & derivatives , Alanine/adverse effects , Alanine/analogs & derivatives , Antibodies, Monoclonal, Humanized/adverse effects , Azithromycin/adverse effects , Chemical and Drug Induced Liver Injury/epidemiology , Chemical and Drug Induced Liver Injury/etiology , Chloroquine/adverse effects , Databases, Pharmaceutical , Diarrhea/chemically induced , Diarrhea/epidemiology , Drug Combinations , Drug Eruptions/epidemiology , Drug Eruptions/etiology , Drug Repositioning , Female , Humans , Hydroxychloroquine/adverse effects , Long QT Syndrome/chemically induced , Long QT Syndrome/epidemiology , Lopinavir/adverse effects , Male , Nausea/chemically induced , Nausea/epidemiology , Oseltamivir/adverse effects , Ritonavir/adverse effects , Sex Distribution , Sex Factors , Vomiting/chemically induced , Vomiting/epidemiology
8.
Int J Cardiol ; 324: 255-260, 2021 02 01.
Article in English | MEDLINE | ID: covidwho-1065148

ABSTRACT

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.


Subject(s)
COVID-19/drug therapy , COVID-19/epidemiology , Cardiotoxicity/epidemiology , Lopinavir/administration & dosage , Lopinavir/adverse effects , Pharmacovigilance , Ritonavir/administration & dosage , Ritonavir/adverse effects , Aged , Aged, 80 and over , COVID-19/diagnosis , Cardiotoxicity/diagnosis , Drug Combinations , Electrocardiography/drug effects , Electrocardiography/trends , Female , France/epidemiology , HIV Protease Inhibitors/administration & dosage , HIV Protease Inhibitors/adverse effects , Humans , Long QT Syndrome/chemically induced , Long QT Syndrome/diagnosis , Long QT Syndrome/epidemiology , Male , Middle Aged , Potassium Channel Blockers/administration & dosage , Potassium Channel Blockers/adverse effects
9.
Int J Cardiol ; 331: 333-339, 2021 05 15.
Article in English | MEDLINE | ID: covidwho-1056682

ABSTRACT

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.


Subject(s)
Arrhythmias, Cardiac/diagnosis , Artificial Intelligence , COVID-19/drug therapy , Electrocardiography , Long QT Syndrome , Adult , Arrhythmias, Cardiac/chemically induced , Azithromycin/adverse effects , Azithromycin/therapeutic use , Female , Humans , Hydroxychloroquine/adverse effects , Hydroxychloroquine/therapeutic use , Long QT Syndrome/epidemiology , Male , Middle Aged , Pandemics
10.
JACC Clin Electrophysiol ; 7(1): 16-25, 2021 01.
Article in English | MEDLINE | ID: covidwho-1023623

ABSTRACT

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.


Subject(s)
Anti-Bacterial Agents/adverse effects , Azithromycin/adverse effects , COVID-19/drug therapy , Enzyme Inhibitors/adverse effects , Hydroxychloroquine/adverse effects , Long QT Syndrome/chemically induced , Age Factors , Aged , Aged, 80 and over , Body Mass Index , COVID-19/epidemiology , Comorbidity , Creatinine/blood , Drug Therapy, Combination , Electrocardiography , Female , Heart Failure/epidemiology , Hospitalization , Humans , Long QT Syndrome/epidemiology , Male , Middle Aged , Mortality , Proportional Hazards Models , Risk Factors , SARS-CoV-2 , Troponin I/blood
11.
Int J Clin Pract ; 75(2): e13896, 2021 Feb.
Article in English | MEDLINE | ID: covidwho-1010920

ABSTRACT

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.


Subject(s)
Anti-Bacterial Agents/therapeutic use , Arrhythmias, Cardiac/drug therapy , Azithromycin/therapeutic use , COVID-19/drug therapy , Hydroxychloroquine/therapeutic use , Long QT Syndrome/drug therapy , Adult , Aged , Arrhythmias, Cardiac/epidemiology , COVID-19/epidemiology , Comorbidity , Drug Therapy, Combination , Electrocardiography , Female , Humans , Long QT Syndrome/epidemiology , Male , Middle Aged , Retrospective Studies , SARS-CoV-2
12.
Therapie ; 75(4): 371-379, 2020.
Article in English | MEDLINE | ID: covidwho-1005755

ABSTRACT

INTRODUCTION: COVID-19 is an unprecedented challenge for physicians and scientists. Several publicized drugs are being used with not much evidence of their efficacy such as hydroxychloroquine, azithromycin or lopinavir-ritonavir. Yet, the cardiac safety of these drugs in COVID-19 deserves scrutiny as they are known to foster cardiac adverse ADRs, notably QTc interval prolongation on the electrocardiogram and its arrhythmogenic consequences. METHODS: Since March 27th, 2020, the French Pharmacovigilance Network directed all cardiac adverse drug reactions associated with "off-label" use of hydroxychloroquine, azithromycin and lopinavir-ritonavir in COVID-19 to the Nice Regional Center of Pharmacovigilance. Each Regional Center of Pharmacovigilance first assessed causality of drugs. We performed a specific analysis of these cardiac adverse drug reactions amidst an array of risk factors, reassessed the electrocardiograms and estimated their incidence in coronavirus disease 2019. RESULTS: In one month, 120 reports of cardiac adverse drug reactions have been notified, 103 of which associated with hydroxychloroquine alone (86%), or associated with azithromycin (60%). Their estimated incidence is 0.77% to 1.54% of all patients, notwithstanding strong underreporting. Lopinavir-ritonavir came third with 17 reports (14%) and chloroquine fourth with 3 reports (2.5%). There were 8 sudden, unexplained or aborted deaths (7%), 8 ventricular arrhythmias (7%), 90 reports of prolonged QTc (75%) most of them "serious" (64%), 48 of which proved ≥ 500ms, 20 reports of severe conduction disorders (17%) and 5 reports of other cardiac causes (4%). Six reports derived from automedication. DISCUSSION AND CONCLUSION: "Off-label" use of treatments in COVID-19 increases the risk of cardiac ADRs, some of them avoidable. Even if these drugs are perceived as familiar, they are used in patients with added risk factors caused by infection. Precautions should be taken to mitigate the risk, even if they will be proven efficacious.


Subject(s)
Coronavirus Infections/drug therapy , Heart Diseases/chemically induced , Off-Label Use , Pharmacovigilance , Pneumonia, Viral/drug therapy , Adverse Drug Reaction Reporting Systems/statistics & numerical data , Aged , Azithromycin/administration & dosage , Azithromycin/adverse effects , COVID-19 , Chloroquine/administration & dosage , Chloroquine/adverse effects , Drug Combinations , Electrocardiography , Female , France/epidemiology , Heart Diseases/epidemiology , Humans , Hydroxychloroquine/administration & dosage , Hydroxychloroquine/adverse effects , Long QT Syndrome/chemically induced , Long QT Syndrome/epidemiology , Lopinavir/administration & dosage , Lopinavir/adverse effects , Male , Middle Aged , Pandemics , Risk Factors , Ritonavir/administration & dosage , Ritonavir/adverse effects
13.
Cardiovasc Toxicol ; 21(4): 314-321, 2021 04.
Article in English | MEDLINE | ID: covidwho-1002172

ABSTRACT

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.


Subject(s)
COVID-19/drug therapy , COVID-19/epidemiology , Chloroquine/adverse effects , Electrocardiography/drug effects , Long QT Syndrome/chemically induced , Long QT Syndrome/epidemiology , Aged , COVID-19/physiopathology , Cohort Studies , Electrocardiography/trends , Female , Heart Rate/drug effects , Heart Rate/physiology , Humans , Long QT Syndrome/physiopathology , Male , Middle Aged , Netherlands/epidemiology , Risk Factors
14.
Kardiologiia ; 60(7): 11-14, 2020 Aug 11.
Article in Russian | MEDLINE | ID: covidwho-994754

ABSTRACT

Since the first case recorded in the end of 2019, the virus SARS-CоV-2 and the related lung disease COVID-19 have spread over the world and became a threat for public health. The drugs used for treatment of this disease (azithromycin and hydroxychloroquine) can prolong the QT interval on the electrocardiogram to increase the risk of pirouette tachycardia and sudden cardiac death. This article presents a review of potential risks related with the drug treatment of COVID-19 and provides recommendations for management of patients during the pandemic.


Subject(s)
Betacoronavirus , Coronavirus Infections , Long QT Syndrome , Pandemics , Pneumonia, Viral , COVID-19 , Humans , Long QT Syndrome/epidemiology , SARS-CoV-2
15.
J Antimicrob Chemother ; 76(2): 482-486, 2021 01 19.
Article in English | MEDLINE | ID: covidwho-939573

ABSTRACT

BACKGROUND: Combination therapy with hydroxychloroquine and darunavir/ritonavir or lopinavir/ritonavir has been suggested as an approach to improve the outcome of patients with moderate/severe COVID-19 infection. OBJECTIVES: To examine the safety of combination therapy with hydroxychloroquine and darunavir/ritonavir or lopinavir/ritonavir. METHODS: This was an observational cohort study of patients hospitalized for COVID-19 pneumonia treated with hydroxychloroquine and darunavir/ritonavir or lopinavir/ritonavir. Clinical evaluations, electrocardiograms and the pharmacokinetics of hydroxychloroquine, darunavir and lopinavir were examined according to clinical practice and guidelines. RESULTS: Twenty-one patients received hydroxychloroquine with lopinavir/ritonavir (median age 68 years; 10 males) and 25 received hydroxychloroquine with darunavir/ritonavir (median age 71 years; 15 males). During treatment, eight patients (17.4%) developed ECG abnormalities. Ten patients discontinued treatment, including seven for ECG abnormalities a median of 5 (range 2-6) days after starting treatment. All ECG abnormalities reversed 1-2 days after interrupting treatment. Four patients died within 14 days. ECG abnormalities were significantly associated with age over 70 years, coexisting conditions (such as hypertension, chronic cardiovascular disease and kidney failure) and initial potential drug interactions, but not with the hydroxychloroquine concentration. CONCLUSIONS: Of the patients with COVID-19 who received hydroxychloroquine with lopinavir or darunavir, 17% had ECG abnormalities, mainly related to age or in those with a history of cardiovascular disease.


Subject(s)
Antiviral Agents/adverse effects , COVID-19/drug therapy , Darunavir/adverse effects , Hydroxychloroquine/adverse effects , Lopinavir/adverse effects , Antiviral Agents/administration & dosage , Antiviral Agents/blood , Antiviral Agents/therapeutic use , COVID-19/epidemiology , Cohort Studies , Darunavir/administration & dosage , Darunavir/blood , Darunavir/therapeutic use , Drug Therapy, Combination , Electrocardiography , France , Humans , Hydroxychloroquine/administration & dosage , Hydroxychloroquine/blood , Hydroxychloroquine/therapeutic use , Long QT Syndrome/chemically induced , Long QT Syndrome/epidemiology , Lopinavir/administration & dosage , Lopinavir/blood , Lopinavir/therapeutic use , SARS-CoV-2 , Severity of Illness Index , Treatment Outcome
16.
Expert Rev Pharmacoecon Outcomes Res ; 21(1): 159-168, 2021 Feb.
Article in English | MEDLINE | ID: covidwho-926348

ABSTRACT

Background: Hydroxychloroquine, an antimalarial drug, combined with azithromycin has been considered a potential treatment for COVID-19. However, these drugs may cause electrocardiogram QT prolongation (QTp) and torsade de Pointes (TdP). We examined potential safety signals for these cardiac arrhythmias. Methods: Using the OpenVigil 2.1 MedDRA platform, we mined data from the U.S. Food and Drug Administration's Adverse Event Reporting System (FAERS) from December 2019 to June 2020. We extracted individual case safety reports based on exposures of seven antimalarial drugs, azithromycin, and combinations. All other drugs in FAERS served as controls. Events of interest included QTp and TdP, with associations between drug exposures and events expressed as adjusted Reporting-Odds-Ratios (aRORs) and confidence intervals. The lower end of aROR 95% confidence interval >1 was used as the statistically significant signal detection threshold. Results: QTp safety signals were found for hydroxychloroquine[aROR:11.70 (10.40-13.16)], chloroquine[aROR:18.97 (11.30-31.87)], quinine[aROR:16.66 (10.18-27.25)], atovaquone[aROR:6.91 (4.14-11.56)], azithromycin alone [aROR:28.02 (22.87-34.32)] and hydroxychloroquine + azithromycin [aROR:75.23 (51.15-110.66)]. TdP safety signals were found for hydroxychloroquine [aROR: 5.62 (4.94-6.38)], chloroquine[aROR:49.37 (30.63-79.58)], and hydroxychloroquine + azithromycin[aROR:33.09 (21.22-51.61)]. Conclusion: Hydroxychloroquine/chloroquine and/or azithromycin was associated with QTp/TdP safety signals and their use should be monitored carefully.


Subject(s)
Anti-Bacterial Agents/adverse effects , Anti-Bacterial Agents/therapeutic use , Antimalarials/adverse effects , Antimalarials/therapeutic use , Arrhythmias, Cardiac/chemically induced , Azithromycin/adverse effects , Azithromycin/therapeutic use , COVID-19/drug therapy , Pharmacovigilance , Adverse Drug Reaction Reporting Systems , Drug Therapy, Combination , Electrocardiography/drug effects , Humans , Long QT Syndrome/chemically induced , Long QT Syndrome/epidemiology , Torsades de Pointes/chemically induced , Torsades de Pointes/epidemiology , United States , United States Food and Drug Administration
17.
Eur J Clin Invest ; 51(2): e13428, 2021 Feb.
Article in English | MEDLINE | ID: covidwho-845033

ABSTRACT

BACKGROUND: The coronavirus disease 2019 (COVID-19) pandemic has affected millions of people worldwide resulting in significant morbidity and mortality. Arrhythmias are prevalent and reportedly, the second most common complication. Several mechanistic pathways are proposed to explain the pro-arrhythmic effects of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. A number of treatment approaches have been trialled, each with its inherent unique challenges. This rapid systematic review aimed to examine the current incidence and available treatment of arrhythmias in COVID-19, as well as barriers to implementation. METHODS: Our search of scientific databases identified relevant published studies from 1 January 2000 until 1 June 2020. We also searched Google Scholar for grey literature. We identified 1729 publications of which 1704 were excluded. RESULTS: The incidence and nature of arrhythmias in the setting of COVID-19 were poorly documented across studies. The cumulative incidence of arrhythmia across studies of hospitalised patients was 6.9%. Drug-induced long QT syndrome secondary to antimalarial and antimicrobial therapy was a significant contributor to arrhythmia formation, with an incidence of 14.15%. Torsades de pointes (TdP) and sudden cardiac death (SCD) were reported. Treatment strategies aim to minimise this through risk stratification and regular monitoring of corrected QT interval (QTc). CONCLUSION: Patients with SARS-CoV-2 are at an increased risk of arrhythmias. Drug therapy is pro-arrhythmogenic and may result in TdP and SCD in these patients. Risk assessment and regular QTc monitoring are imperative for safety during the treatment course. Further studies are needed to guide future decision-making.


Subject(s)
Arrhythmias, Cardiac/etiology , COVID-19/complications , Long QT Syndrome/chemically induced , Anti-Arrhythmia Agents/therapeutic use , Anti-Bacterial Agents/adverse effects , Antimalarials/adverse effects , Arrhythmias, Cardiac/epidemiology , Arrhythmias, Cardiac/therapy , Atrial Fibrillation/epidemiology , Atrial Fibrillation/etiology , Atrial Fibrillation/therapy , Atrial Flutter/epidemiology , Atrial Flutter/etiology , Atrial Flutter/therapy , Azithromycin/adverse effects , Bradycardia/epidemiology , Bradycardia/etiology , Bradycardia/therapy , COVID-19/drug therapy , Cardiac Pacing, Artificial/methods , Death, Sudden, Cardiac/epidemiology , Death, Sudden, Cardiac/etiology , Electric Countershock/methods , Hospitalization , Humans , Hydroxychloroquine/adverse effects , Incidence , Long QT Syndrome/epidemiology , Long QT Syndrome/therapy , SARS-CoV-2 , Tachycardia, Ventricular/epidemiology , Tachycardia, Ventricular/etiology , Tachycardia, Ventricular/therapy , Torsades de Pointes/epidemiology , Torsades de Pointes/etiology , Torsades de Pointes/therapy , Ventricular Fibrillation/epidemiology , Ventricular Fibrillation/etiology , Ventricular Fibrillation/therapy
20.
J Interv Card Electrophysiol ; 59(2): 337-345, 2020 Nov.
Article in English | MEDLINE | ID: covidwho-640049

ABSTRACT

PURPOSE: Hydroxychloroquine, chloroquine, and azithromycin have been used for treatment of COVID-19, but may cause QT prolongation. Minority populations are disproportionately impacted by COVID-19. This study evaluates the risk of QT prolongation and subsequent outcomes after administration of these medications in largely underrepresented minority COVID-19 patients. METHODS: We conducted an observational study on hospitalized COVID-19 patients in the Montefiore Health System (Bronx, NY). We examined electrocardiograms (ECG) pre/post-medication initiation to evaluate QTc, HR, QRS duration, and presence of other arrhythmias. RESULTS: One hundred five patients (mean age 67 years; 44.8% F) were analyzed. The median time from the first dose of any treatment to post-medication ECG was 2 days (IQR: 1-3). QTc in men increased from baseline (440 vs 455 ms, p < 0.001), as well as in women (438 vs 463 ms, p < 0.001). The proportion of patients with QT prolongation increased significantly (14.3% vs 34.3%, p < 0.001) even when adjusted for electrolyte abnormalities. The number of patients whose QTc > 500 ms was significantly increased after treatment (16.2% vs. 4.8%, p < 0.01). Patients with either QTc > 500 ms or an increase of 60 ms had a higher frequency of death (47.6% vs. 22.6%, p = 0.02) with an odds ratio of 3.1 (95% CI: 1.1-8.7). Adjusting for race/ethnicity yielded no significant associations. CONCLUSIONS: Hydroxychloroquine, chloroquine, and/or azithromycin were associated with QTc prolongation but did not result in fatal arrhythmias. Our findings suggest that any harm is unlikely to outweigh potential benefits of treatment. Careful risk-benefit analyses for individual patients should guide the use of these medications. Randomized control trials are necessary to evaluate their efficacies.


Subject(s)
Antimalarials/adverse effects , Azithromycin/adverse effects , Coronavirus Infections/drug therapy , Electrocardiography/methods , Long QT Syndrome/chemically induced , Pneumonia, Viral/drug therapy , Age Distribution , Aged , Aged, 80 and over , Antimalarials/administration & dosage , Azithromycin/administration & dosage , COVID-19 , Chloroquine/administration & dosage , Chloroquine/adverse effects , Coronavirus Infections/diagnosis , Coronavirus Infections/epidemiology , Female , Follow-Up Studies , Hospitalization/statistics & numerical data , Humans , Hydroxychloroquine/administration & dosage , Hydroxychloroquine/adverse effects , Incidence , Long QT Syndrome/diagnostic imaging , Long QT Syndrome/drug therapy , Long QT Syndrome/epidemiology , Male , Middle Aged , Pandemics/prevention & control , Pandemics/statistics & numerical data , Pneumonia, Viral/diagnosis , Pneumonia, Viral/epidemiology , Risk Assessment , Sex Distribution , Urban Population
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