key: cord-353058-3r6jw5ij
authors: Crotti, Lia; Arbelo, Elena
title: COVID-19 treatments, QT interval and arrhythmic risk: the need for an international Registry on Arrhythmias
date: 2020-05-26
journal: Heart Rhythm
DOI: 10.1016/j.hrthm.2020.05.024
sha: 
doc_id: 353058
cord_uid: 3r6jw5ij

nan

In December 2019, the Chinese public health authorities made public several cases of acute respiratory syndrome in the city of Wuhan caused by the novel SARS-CoV2 virus 1, 2 . In our hyperconnected world, the initial outbreak experienced unprecedented dissemination and has now become this century's worst pandemic, with more than 4 million people infected and almost 300,000 deaths so far 3 .

To manage the emergency situation, several "off-label" treatment options have been implemented worldwide based on limited in vitro or small observational studies. These drugs include chloroquine/hydroxychloroquine, protease inhibitors, remdesivir, azithromycin, glucocorticoids, and biological agents like tocilizumab, among others 4 .

One major concern with these drugs is the possibility of QTc prolongation and torsade de pointes/sudden death. This risk is amplified by drug-to-drug interactions (which may increase bioavailability and, consequently, side effects), concomitant use of other QTc-prolonging drugs and/or the presence of ion disbalances (hypokalemia, hypomagnesemia and/or hypocalcemia). A second concern is the risk of conduction disturbances; however, these appear to be rare and mostly linked to long-term treatment 4 . Consequently, at an early stage in the COVID-19 pandemic, it became apparent that in order to prevent drug-induced pro-arrhythmia, standardized protocols were needed, and several guidance documents by international associations and arrhythmia/QTc experts have been published [4] [5] [6] [7] .

In the present issue of Heart Rhythm, Jain and co-authors 8 retrospectively analyzed 2006 ECGs collected during a 2-week period from 524 unique patients, most of them with a diagnosis of COVID-19. Almost 20% of these patients showed a QT prolongation defined as a QTc >470 msec for a QRS below 120 msec or a QTc >500 msec in case of prolonged QRS. Whenever a QT prolongation was identified, the electrophysiology consult service was activated and a support was given to the primary team caring for the patients. The support was mainly based on recommendation regarding electrolyte supplementation, discontinuation of nonessential QT prolonging drugs and a discussion about risks and benefits of continuing COVID-19 treatment. In one third of the patients COVID-19 treatments, most commonly hydroxychloroquine rarely in association with atazanavir or azithromycin were discontinued. None of their patients developed torsade de pointes and only one patient had sustained ventricular tachycardia but in the setting of an acute myocardial infarction. It is also true that not all patients were monitored, and therefore as clearly highlighted by the authors, some arrhythmias may not have been identified, but these data are anyhow reassuring. The authors are confident that their monitoring system played a major role in the low incidence of arrhythmic events observed. That is possibly true, but unfortunately, no ECG data are available to directly look at the QT response to the electrophysiologists' recommendations and a control group is missing. Furthermore, their data do not show a clearly reduced event rate compared to other observational studies so far performed. Indeed, there are already few studies that evaluated QTc and arrhythmic risk in hospitalized COVID-19 patients treated with different QT-prolonging drugs (i.e. hydroxychloroquine/chloroquine, azithromycin, lopinavir/ritonavir). The first study by Chorin E et al 9 showed in a population of 85 COVID-19 patients treated with the association of hydroxychloroquine and azithromycin that a QT prolongation was present in the vast majority of treated patients with a 30% who increased their QTc more than 40 msec and 11% who showed a severe prolongation (QTc>500 msec). Despite that, none of them developed torsades de pointes 9 . Saleh M et al 10 evaluated 201 COVID-19 patients who during hospitalization received chloroquine/hydroxychloroquine as a monotherapy (61%) or in association with azithromycin (59%). Similar to previous study 9% of patients showed a QTc>500 msec on treatment (3.5% had discontinuation of therapy), but no torsades de pointes or arrhythmic death were reported. While in the study by Jain et al 8 a clear strategy was employed to reduce the risk of arrhythmias potentially related to QT prolongation, in the studies by Chorin E et al and Saleh M et al, no pre-defined strategies were presented 9-10 ; nevertheless, it is likely that if QTc was monitored, corrections to avoid excessive QT prolongation ( i.e. avoid electrolytes abnormalities and association with additional QT prolonging drugs when possible) were implemented even without a precise scheme. A major difference between these studies is that in the study by Jain et al 8 one third of the patients discontinued therapy, while this happened only in 2.5% of the patients in the one by Saleh et al 9 . In the presence of a potentially lethal disease, discontinuation of an effective therapy may be dangerous, but this is unfortunately not the case. Indeed, the underlying evidence supporting the current COVID-19 treatment is weak and we are in critical need of well-designed clinical trials.

As new data with higher levels of evidence emerges, the scenery of treatment options in COVID-19 will rapidly evolve. Still, whatever the medication, we should always bear in mind the potential risk of QTc prolongation, drug-to-drug interactions and drug-induced pro-arrhythmia. Indeed, very recently, several studies have questioned the effectiveness of hydroxychloroquine 11, 12 , lopinavir-ritonavir 13 and remdesivir 14 . Sadly, only the lopinavir-ritonavir trial specifically assessed QTc and pro-arrhythmia and showed no significant QTc prolongation nor serious arrhythmic events in either arm (95 patients in the lopinavir-ritonavir group and 99 patients in the standard care group) 13 . These data are clearly important to be able to better balance risk and benefits of choices (i.e. arrhythmic risk in a protected environment vs effectiveness of therapy in reducing mortality and improving outcomes), and should therefore be systematically collected. To favor the collection of these data in a big number of affected patients and to monitor the occurrence of arrhythmic events in the context of the SARS-CoV2 infection, the International Registry on Arrhythmias in COVID-19 (COVIDAR), was recently established and endorsed by EHRA and ERN GUARD-Heart. This Registry, if successful, will provide a valuable support in the decision making process.

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