key: cord-1003065-ez1ae9cd
authors: Pallotto, Carlo; Suardi, Lorenzo R.; Gabbuti, Andrea; Esperti, Sara; Mecocci, Lorenzo; Blanc, Pierluigi
title: Potential remdesivir‐related transient bradycardia in patients with coronavirus disease 2019 (COVID‐19)
date: 2021-03-03
journal: J Med Virol
DOI: 10.1002/jmv.26898
sha: b826eac7c928153b16e6fc6bb0c5d5fc0f5acc3a
doc_id: 1003065
cord_uid: ez1ae9cd

BACKGROUND The coronavirus disease 2019 (COVID-19) is still a global concern with elevated morbidity and mortality. Between several candidates, only a few drugs appeared to be promising. One of them, remdesivir (RDV), was recently approved by the European Medicines Agency for COVID-19 treatment but our knowledge about its potential side effects are still scarce. OBJECTIVES To describe potential RDV-related cardiologic adverse events. PATIENTS AND METHODS Retrospective observational case series. We consecutively enrolled all the patients admitted to our ward with COVID-19 from September 14th to October 14th. RESULTS Twenty patients were treated with RDV during the study period. We observed a tendency to develop bradycardia in association with RDV administration in 12/20 patients with no other clinically relevant alterations. DISCUSSION AND CONCLUSIONS We pointed out this possible potential adverse event related to RDV administration. More studies are necessary to better clarify our findings and their potential association with RDV treatment. This article is protected by copyright. All rights reserved.

To the Editor, Coronavirus disease 2019 (COVID-19) is still a global concern with elevated morbidity and mortality. [1] [2] [3] Several drugs were evaluated, but, until now, only remdesivir (RDV), an inhibitor of the viral RNAdependent RNA polymerase, was approved for COVID-19 therapy. 4, 5 Although RDV treatment was quite well described, [4] [5] [6] the knowledge about RDV-related adverse events is still scarce and mostly limited to case reports describing hepatotoxicity and skin reactions. 7 Here, we describe our experience about COVID-19 treatment with RDV focusing on possible RDV-related cardiologic adverse events.

We retrospectively evaluated all the patients consecutively admitted to our ward with a confirmed diagnosis of COVID-19 from September 14th to October 14th, 2020. The study population was divided into two groups, according to RDV administration (cases treated with RDV were defined as patients, whereas cases who did not receive RDV were defined as controls). We collected data about demographic and clinical characteristics, treatments, and adverse events; heart rates (HRs) were collected three to six times per day according to patients' clinical status.

Clinical characteristics and laboratory data were collected using an ad hoc case report form. Data selection was based on a previous work of this group about risk factors for severe illness in COVID-19 patients. 2 In the patients' group, we compared median HR during RDV administration with the median HR of the 3 days before RDV administration and the median HR of the 3 days after RDV administration. Moreover, we compared incidence of bradycardia between patients and controls. RDV Forty-six patients were observed in the study period, 20 patients and 26 controls. Table 1 describes patients' and controls' clinical characteristics at admission and outcomes. In . were detected in the whole study population. Table 2 Only Pt 6 had a negative outcome.

As shown in Table 1 , bradycardia appeared to be more frequent in the patients' group (60% vs. 23%, p = .016). To better understand this finding, a univariate and a multivariate logistic regression was managed (Table 3 ). Both at univariate and multivariate analysis, age > 65 years and RDV treatment were significantly associated with bradycardia.

RDV was shown to reduce the recovery time from COVID-19, with no effect on mortality rates, 9 and it was recently approved by EMA. 8 Although some studies were published on this field and many others are ongoing, our knowledge about RDV tolerability is still scarce; hepatotoxicity and skin reactions were the only adverse events described at the moment. 7 On the contrary, such events

were not observed in our study. Moreover, we noticed a tendency to develop bradycardia during RDV treatment. Bradycardia tended to resolve after RDV discontinuation. These HR variations reached the threshold of statistical significance in some cases (Table 2) .

Moreover, incidence of bradycardia was higher in the patients' group and its association with RDV administration was confirmed also by multivariate logistic regression.

In our experience, bradycardia did not induce any consequences of clinical relevance: patients were asymptomatic, blood pressure remained in the normal range, and no ECG alterations were observed. However, this phenomenon appeared to be worthy of consideration, especially in patients who were chronically under treatment with bradycardiainducing drugs such as beta-blockers.

To the best of authors' knowledge, this is the first report of potential RDV-related bradycardia. As a consequence, we are not able to provide a full "pathogenetic" explanation.

This study has some limitations, such as the limited sample size and its observational design. Nevertheless, it pointed out a new aspect of RDV treatment that could be of clinical interest.

In conclusion, a potential-at least time-association between bradycardia and RDV administration was observed. Clinicians should be aware of this potential RDV side effect. More extensive studies are necessary to clarify this finding. 

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