The effect of 5-day course of hydroxychloroquine and azithromycin combination on QT interval in non-ICU COVID19(+) patients
MD ⁎ Nijad Bakhshaliyev, MD Mahmut Uluganyan, MD Asim Enhos, MD Erdem Karacop, MD Ramazan Ozdemir
Journal of Electrocardiology, doi:10.1016/j.jelectrocard.2020.08.008
Background: The combination of Hydroxychloroquine (HCQ) and azithromycin showed effectiveness as a treatment for COVID-19 and is being used widely all around the world. Despite that those drugs are known to cause prolonged QT interval individually there is no study assessing the impact of this combination on electrocardiography (ECG). This study aimed to assess the impact of a 5-day course of HCQ and azithromycin combination on ECG in non-ICU COVID19(+) patients. Methods: In this retrospective observational study, we enrolled 109 COVID19(+) patients who required non-ICU hospitalization. All patients received 5-day protocol of HCQ and azithromycin combination. On-treatment ECGs were repeated 3-6 h after the second HCQ loading dose and 48-72 h after the first dose of the combination. ECGs were assessed in terms of rhythm, PR interval, QRS duration, QT and QTc intervals. Baseline and ontreatment ECG findings were compared. Demographic characteristics, laboratory results were recorded. Daily phone call-visit or bed-side visit were performed by attending physician. Results: Of the 109 patients included in the study, the mean age was 57.3 ± 14.4 years and 48 (44%) were male. Mean baseline PR interval was 158.47 ± 25.10 ms, QRS duration was 94.00 ± 20.55 ms, QTc interval was 435. 28 ± 32.78 ms, 415.67 ± 28.51, 412.07 ± 25.65 according to Bazett's, Fridericia's and Framingham Heart Study formulas respectively. ΔPR was −2.94 ± 19.93 ms (p = .55), ΔQRS duration was 5.18 ± 8.94 ms (p = .03). ΔQTc interval was 6.64 ± 9.60 ms (p = .5), 10.67 ± 9.9 ms (p = .19), 14.14 ± 9.68 ms (p = .16) according to Bazett's, Fridericia's and Framingham Heart Study formulas respectively. There were no statistically significant differences between QTc intervals. No ventricular tachycardia, ventricular fibrillation or significant conduction delay was seen during follow-up. There was no death or worsening heart function.
Conclusion: The 5-day course of HCQ-AZM combination did not lead to clinically significant QT prolongation and other conduction delays compared to baseline ECG in non-ICU COVID19(+) patients.
References
Anderson, Al-Khatib, Roden, Califf, Institute, Cardiac repolarization: current knowledge, critical gaps, and new approaches to drug development and patient management, Am Heart J
Ben-Zvi, Kivity, Langevitz, Shoenfeld, Hydroxychloroquine: from malaria to autoimmunity, Clin Rev Allergy Immunol
Borba, De, Val, Sampaio, Chloroquine diphosphate in two different dosages as adjunctive therapy of hospitalized patients with severe respiratory syndrome in the context of coronavirus (SARS-CoV-2) infection: Preliminary safety results of a randomized, double-blinded, phase IIb clinical trial (CloroCovid-19 Study), medRxiv
Bruin, Pettersson, Meyboom, Hoes, Leufkens, Anti-HERG activity and the risk of drug-induced arrhythmias and sudden death, Eur Heart J
Caly, Druce, Catton, Jans, Wagstaff, The FDA-approved drug Ivermectin inhibits the replication of SARS-CoV-2 in vitro, Antivir Res
Chen, Wang, Lin, Chronic hydroxychloroquine use associated with QT prolongation and refractory ventricular arrhythmia, Clin Toxicol
Chiang, Sassaroli, Louie, Chen, Stecher et al., Inhibition of HIV-1 replication by hydroxychloroquine: mechanism of action and comparison with zidovudine, Clin Ther
Clemessy, Borron, Baud, Favier, Hantson et al., Hypokalaemia related to acute chloroquine ingestion, Lancet
Dong, Hu, Gao, Discovering drugs to treat coronavirus disease 2019 (COVID-19), Drug Discov & Ther
Fleet, Shariff, Bailey, Comparing two types of macrolide antibiotics for the purpose of assessing population-based drug interactions, BMJ Open
Gautret, Lagier, Parola, Hydroxychloroquine and azithromycin as a treatment of COVID-19: results of an open-label non-randomized clinical trial, Int J Antimicrob Agents
Goldstein, Owens, Nolin, Antimicrobial-associated QT interval prolongation: pointes of interest, Clin Infect Dis
Gupta, Lawrence, Krishnan, Kavinsky, Trohman, Current concepts in the mechanisms and management of drug-induced QT prolongation and torsade de pointes, Am Heart J
Huang, Wu, Cp, Chen C, Azithromycin-induced torsade de pointes, Pacing Clin Electrophysiol
Kezerashvili, Khattak, Barsky, Nazari, Fisher, Azithromycin as a cause of QT-interval prolongation and torsade de pointes in the absence of other known precipitating factors, J Interv Card Electrophysiol
Lee, Vinayagamoorthy, Han, Association of polymorphisms of cytochrome P450 2D6 with blood hydroxychloroquine levels in patients with systemic lupus erythematosus, Arthritis Rheum
Lode, The pharmacokinetics of azithromycin and their clinical significance, Eur J Clin Microbiol Infect Dis
Matsunaga, Oki, Prigollini, A case of QT-interval prolongation precipitated by azithromycin, The New Zealand Medical Journal (Online)
Milberg, Eckardt, Bruns, Divergent proarrhythmic potential of macrolide antibiotics despite similar QT prolongation: fast phase 3 repolarization prevents early afterdepolarizations and torsade de pointes, J Pharmacol Exp Ther
Mortensen, Halm, Pugh, Association of Azithromycin with Mortality and Cardiovascular Events among Older Patients Hospitalized with Pneumonia, JAMA
Organization, WHO director-General's opening remarks at the media briefing on COVID-19-11
Pruchnicki, Good, Walson, Severe hydroxychloroquine poisoning reversed with diazepam, J Toxicol Clin Toxicol
Ray, Murray, Hall, Arbogast, Stein, Azithromycin and the risk of cardiovascular death, N Engl J Med
Roden, Harrington, Poppas, Russo, Considerations for Drug Interactions on QTc in Exploratory COVID-19, Treatment. Circulation
Russo, Puzio, Siniscalchi, Azithromycin-induced QT prolongation in elderly patient, ACTA BIOMEDICA-ATENEO PARMENSE
Singlas, Clinical pharmacokinetics of azithromycin, Pathologie-biologie
Svanström, Pasternak, Hviid, Use of azithromycin and death from cardiovascular causes, N Engl J Med
Tett, Mclachlan, Day, Cutler, Insights from pharmacokinetic and pharmacodynamic studies of hydroxychloroquine, Agents Actions Suppl
Wang, Lin, Huang, Hydroxychloroquine-inhibited dengue virus is associated with host defense machinery, J Interf Cytokine Res
Yogasundaram, Putko, Tien, Hydroxychloroquine-induced cardiomyopathy: case report, pathophysiology, diagnosis, and treatment, Can J Cardiol
Zhu, Zhang, Wang, A novel coronavirus from patients with pneumonia in China, N Engl J Med
