Proarrhythmia assessment in treatment with hydroxychloroquine and azithromycin hospitalized elderly COVID-19 patients - our experience

Abstract

The aim of our study was to characterize the repolarization disorders propensity induced by drug-drug interaction. In this observational retrospective study, we report our experience on all elderly patients with ascertained diagnosis of coronavirus disease 2019 through nasopharyngeal swab with real time-polymerase chain reaction at our Pugliese-Ciaccio hospital in Catanzaro, who received hydroxychloroquine (HCQ), with or without azithromycin (AZY). 33 hospitalized patients were examined. We calculated QT value, cQT, QT dispersion, and cQT dispersion and examined possible progression on the basal electrocardiogram (T0) and after the insertion of the drug (T1). The QT value is increased by T0 vs T1 (370±40.74 vs 420±36.91 ms; P=0.000), as well as the cQT value (408±25.40 vs 451.54±58.81; P=0.003), the QT dispersion (QTd: 36.36±14.53 vs 50.90±13.12 ms; P=0.000); the dispersion of cQTc (cQTd 46.27±18.72 vs 63.18±21.93 ms; P=0.001). The ∆QT was 37.44±44.09 while the ∆cQT was 32.01±56.47). The main determinant of QTc prolongation is the number of drug at risk of prolongation of the QT that could influence the ventricular repolarization phase. The use of HCQ in combination with AZY, in patients suffering from severe acute respiratory syndrome-related coronavirus-2, can favor the onset of serious side effects, even potentially fatal. Finally, the measures of QTd and cQTd confirmed additional electrocardiographic parameters useful in identifying patients being treated with drugs at risk of potential adverse arrhythmic events following drug interaction. Introduction As of 17 October 2020, the number of severe acute respiratory syndrome-related coronavirus-2 (SARS-CoV-2) infected subjects in the world is 39.5 million, with a mortality of 1.11 million patients (3.09%). As we still do not have an effective therapy for SARS-CoV-2 patients are treated with several non-specific drugs. Preliminary studies had shown a promising effect of high-dose hydroxychloroquine (HCQ) in reducing SARS-CoV-2 viral load in hospitalized coronavirus disease 2019 (COVID19) patients, with enhanced effects in combination with azithromycin (AZY) or various antiviral drugs.1,2 HCQ is an older antimalarial drug, first approved in 1955 by the United States Food and Drug Administration (FDA), also used in longterm treatment of connective tissue diseases, widely available and economically viable and has been regarded as generally safe and well tolerated in patients treated for chronic inflammation. It is postulated to exert a direct antiviral activity by increasing intracellular pH resulting in decreased phago-lysosome fusion, impairing viral receptor glycosylation. In addition, it has immune-modulating effect by inhibiting toll-like receptor signaling, decreasing production of cytokines especially interleukin (IL)-1 and IL-6.3 Prior data also suggests a potential anti-thrombotic effect.4 However, HCQ prolongs the QT interval due to blocking of the potassium internal cell current.5-7 This effect may be particularly enhanced when combined with other drugs which may in themselves prolong the QT interval, with a consequent increased risk of druginduced proarrhythmia, conduction block and ventricular arrhythmias, sometimes fatal. Azithromycin, a macrolide antibiotic has in vitro antiviral properties such as decreased viral replication, blocking entrance into host cells, and a potential immunomodulating effect.8 An in vitro study demonstrated synergistic activity of the combination of hydroxychloroquine and azithromycin against SARS-CoV-2.9 Although widely used, azithromycin has also been increasingly recognized for risks of QT interval prolongation and sudden death. The information relating to the safety of the use of these drugs, alone or in combination in elderly COVID-19 patients, particularly if in polypharmacy, in addition to being contradictory, indicated an uncertain benefit in terms of efficacy with a safety profile burdened by risks. The US FDA as of June 15, 2020 has revoked the prior emergency use authorization to use hydroxychloroquine and chloroquine to treat COVID-19 in certain hospitalized patients when clinical trial data is unavailable or participation is not feasible.10 Currently, in light of the latest results available in literature, the authorization to use the HCQ offlabel, outside of clinical studies, has been