The Coronavirus disease 2019 (COVID-19) first appeared in Wuhan, China, in December 2019 and was stated a pandemic by the world health organization (WHO) in March 2020. It rapidly spread around the world and has accounted for millions of global deaths since then. (Chen et al., 2020; Ganesh et al., 2021). The disease is caused by the severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2), an ribonucleic acid (RNA) virus from Corona Viridae family. The infection causes respiratory illness and varies widely in severity from asymptomatic or mild infection to severe pneumonia and subsequent fatal complications, including acute respiratory distress syndrome (ARDS), multiple organ failure, and death. (Grein et al., 2020; Zeng et al., 2021).

Among the antiviral drugs introduced and tested for the treatment of COVID-19, Remdesivir has been particularly used to treat the infection and long-COVID syndrome (Jacinto et al., 2021) during the pandemic after demonstrating its in-vivo and in-vitro inhibitory effects against SARS-CoV-2. (Beigel et al., 2020; Gordon et al., 2020; Gubitosa et al., 2020).

Remdesivir is a nucleotide analog that implicates in viral RNA and inhibits RNA polymerase and viral replication in a wide spectrum of viruses, including SARS-CoV-2, and is potently active in primary human epithelial cells in lung airways. (Gubitosa et al., 2020; Gupta et al., 2020; Gottlieb et al., 2022).

Various studies have indicated its inhibitory effect against the SARS-Cov-2, and it has been approved as an efficient antiviral treatment for hospitalized SARS-Cov-2 patients with moderate to severe infection in all variants of concern. (Beigel et al., 2020; Goldman et al., 2020; Grein et al., 2020; Pasquini et al., 2020; Wang et al., 2020; Pallotto et al., 2021a; Barkas et al., 2021; Brunetti et al., 2021; Gottlieb et al., 2022). A recent randomized controlled trial on non-hospitalized patients infected with COVID-19 who were at higher risk of disease progression showed that Remdesivir treatment reduced the risk of hospitalization and death by 87% compared to placebo. (Gottlieb et al., 2022).

Although its beneficial role in the treatment of COVID-19 has been valued and well described in the literature, evidence on its adverse effect (ADR), especially on the cardiovascular system, is scarce, and the available studies are mainly limited to hepatic, renal, and dermal adverse drug reactions of the drug. (Sarkar et al., 2020; Pallotto et al., 2021a; Pallotto et al., 2021b; Kow et al., 2021). Bradycardia, hypotension, QT interval prolongation, atrial fibrillation, and even cardiac arrest are among the most frequently reported cardiovascular complications attributed to Remdesivir in the literature. (Beigel et al., 2020; Grein et al., 2020; Gupta et al., 2020; Wang et al., 2020). Two potential mechanisms have been proposed for these adverse cardiac effect. First, the Remdesivir active metabolite resembles adenosine triphosphate (ATP). Adenosine may inhibit sinus node automaticity and atrioventricular (AV) node conduction by its chronotropic and dromotropic effects and transiently increases the central vagal tonicity in the heart and also the myocardial repolarization time. These effects may lead to arrhythmias, sinus bradycardia, corrected QT interval (QTc) prolongation and AV node blockage, as have been recently described in the literature. The second mechanism is the Remdesivir affinity to human mitochondrial RNA polymerase, which may possibly result in mitochondrial cardiomyocyte dysfunction and toxicity. (Kumar et al., 2021a; Ching and Lee, 2021; Day et al., 2021; Jacinto et al., 2021; Sanchez-Codez et al., 2021; Touafchia et al., 2021).

Currently, there is limited data on the cardiac adverse effect of Remdesivir except for a few case reports and case series. (Gubitosa et al., 2020; Gupta et al., 2020; Barkas et al., 2021; Ching and Lee, 2021; Day et al., 2021; Jacinto et al., 2021; Selvaraj et al., 2021).

Further comprehensive studies are required to clarify the exact association between Remdesivir and adverse cardiac effects that may lead to bradycardia and other cardiac complications in COVID-19 patients receiving this medication. The present study investigates the incidence of bradycardia in SARS-Cov-2 patients who received Remdesivir and examines the effect of demographic characteristics, underlying risk factors, and the infection severity on developing sinus bradycardia as the most prevalent cardiac complication of Remdesivir. (Lucijanic and Bistrovic, 2022). The results could provide a foundation for future precautions in treating COVID-19 patients receiving Remdesivir.

The present study evaluated the incidence of sinus bradycardia, the most frequent cardiovascular adverse drug reaction of Remdesivir (Lucijanic and Bistrovic, 2022), in patients infected with COVID-19 and also the association between patients’ demographic characteristics, clinical conditions, and the severity of COVID-19 and developing bradycardia.

The prevalence of bradycardia following Remdesivir administration varies widely based on the literature review, from only 3.6% to up to 60%. This wide diversity may be due to the differences in patients’ demographic characteristics, comorbidities and risk factors, medication history, and severity of COVID-19 infection, different study designs and selection bias. Based on the data in the present study, the overall incidence of bradycardia was 27% with 19% HR < 50 bpm, which further supports previous findings on the association between Remdesivir and bradycardia. Palloto et al. found 60% bradycardia incidence after Remdesivir administration versus 23% in the control group. However, their sample size was small (46 patients) and included only 20 patients in the Remdesivir group. They found that the age >65 years and Remdesivir were associated with bradycardia. (Pallotto et al., 2021a). In another retrospective study on 141 patients, the incidence of bradycardia in Remdesivir group was significantly higher (46.8% compared to 27.8% in the control group (OR = 2.15)). (Pallotto et al., 2021b). In a recent study of 180 patients with COVID-19 infection who received Remdesivir, 28.7% developed bradycardia, similar to the incidence of bradycardia in this study. (Kumar et al., 2021a). In the study by Toufchia et al. based on the VigiBase reports, there were only 94 reports of bradycardia among 2,603 patients who received Remdesivir (3.6%), and 17% developed fatal bradycardia. (Touafchia et al., 2021). The low overall incidence of bradycardia in this study could be due to the indirect investigation of Remdesivir complication reports possibly leading to underestimation and selection bias. (Pallotto et al., 2021b; Touafchia et al., 2021). The present study has a large sample size estimatedprioribased on the literature review, and the patients were selected randomly to limit the selection bias and maintain the external validity. Also, the prospective design of this study maintained the direct evaluation of patients in a real-life setting. These, along with controlling potential cofounders by takingcomplete history and concise methods formeasurements to maintain the internal validity, are the strong points of the present study.

The results of the present study showed that the incidence of bradycardia increased over continuous exposure to Remdesivir. The highest incidence of bradycardia occurred within the five sessions of drug administration (21%), with the most HR reduction compared to baseline. Accordingly, no case of bradycardia was observed after the first session of Remdesivir administration. The mean HR decreased significantly with each drug administration. This can be explained by the accumulative toxicity effect of Remdesivir observed by Choi et al. (Choi et al., 2020; Kumar et al., 2021a) who revealed that Remdesivir cell toxicity increases over time. They observed that the viability of cardiomyocytes considerably decreased by a longer treatment with Remdesivir (48 vs. 24 h). (Choi et al., 2020). This observation is also consistent with the study of Bistrovic et al., who found the frequency of bradycardia consistently increased with every further dose of Remdesivir administration, indicating the causal relation between Remdesivir and bradycardia. (Bistrovic et al., 2022). They also observed that the increased level of Remdesivir above the estimated level of peak plasma concentration was potentially associated with QT interval prolongation. The spontaneous beating was almost completely blocked at higher doses of Remdesivir in their experiment. (Choi et al., 2020). Jung et al. also found that the risk of developing serious cardiac complications increases with drug accumulation or overdose. (Jung et al., 2022). They suggested ECG monitoring during Remdesivir administration, especially for severe COVID-19 infection cases as well as those with structural heart diseases. (Choi et al., 2020; Nabati and Parsaee, 2022). we found that cardiovascular disease and Tocilizumab administration associated with bradycardia in multivariable regression model but it was not confirmed in the multivariable model.

In the present study, the mean QTc interval duration shortened significantly after the fifth dose of Remdesivir compared to baseline. This was in contrast with the hypothesis about Remdesivir induced QTc prolongation. Remdesivir has the potential to inhibit the potassium channel encoded by the human ether-a-go-go gene (hERG) and prolongs the ventricular repolarization, causing QT prolongation and torsades de pointes. (Haghjoo et al., 2021; Michaud et al., 2021; Touafchia et al., 2021).In contrast to the present results, the study of Haghjoo et al. on 67 COVID-19 patients treated with Remdesivir showed a significant increase in QTc interval duration but no arrhythmic event such as torsades de pointes (Tdp) was observed. Their only case with critical QTc prolongation was under treatment with Azithromycin and Remdesivir. (Haghjoo et al., 2021). Gupta et al. (Gupta et al., 2020) reported a case with COVID-19 who developed critical QTc prolongation on the third dose of Remdesivir (>555). However, this patient had received Azithromycin as well, which is known to cause QTc prolongation. (Gupta et al., 2020). In a prospective study, Bistrovic et al. investigated 14 patients with COVID-19 infection and found no significant difference in QTc interval and HR after Remdesivir administration. (Bistrovic and Lucijanic, 2021). Even though the mean QTc duration was reduced in the present study, three patients (1.6%) developed extreme QTc prolongation (QTc>500) after Remdesivir administration. It is noteworthy that none of these patients had a history of prior cardiovascular structural diseases and other comorbidities and risk factors for QTc prolongation or a clinically severe COVID-19 infection. They all remained asymptomatic, and none developed consequent arrhythmia related to QTc prolongation. It appears that Remdesivir has a low potential risk of inducing torsades de pointes, as no case of this and other arrhythmias related to QTc prolongation were observed in this neither study nor previous studies. (Gupta et al., 2020; Haghjoo et al., 2021).

While no association was found between COVID-19 severity indicators and bradycardia, previous studies have shown that SARS-CoV-2 can itself induce bradycardia and arrhythmias in severely infected patients. (Oliva et al., 2021). One possible mechanism for this clinical observation is the cardiotoxicity caused by the inflammation and cytokine release during COVID-19 infection, which may increase the vagal tonicity in the heart. Interleukin 6 (IL6), as an important component of cytokine storm, can increase vagal tonicity. Other mechanisms include the impairment of sinus node normal activity due to direct viral inhibition and defects in the autonomic system function due to direct SARS-CoV-2 toxic effects on the nervous system. (Ye et al., 2018; Hu et al., 2020; Oliva et al., 2021). According to these potential mechanisms, the bradycardia development in the context of severe COVID-19 infection regardless of Remdesivir treatment, may be suggestive of the unfavorable infection course as was observed in Kumar et al. study in which developing bradycardia was associated with a higher mortality rate (OR = 6.59). (Kumar et al., 2021b). Nevertheless, the CRP levels were not suggestive of developing bradycardia in patients in the present study (p-value = .41). All studied patients had a favorable prognosis regardless of developing bradycardia and no case of mortality or intubation during hospitalization was observed. The reason could be that most patients in this study had less severe COVID-19 infections and received Remdesivir in an outpatient setting. 19.

Two recent studies revealed that the possibility of developing bradycardia is even higher in less severe COVID-19 cases. (Brunetti et al., 2021; Bistrovic et al., 2022). In a study on 52 patients, The highest HR reduction after Remdesivir treatment was observed in patients with a less clinically severe COVID-19 infection. No association was observed between age, underlying cardiovascular diseases, drugs, and other comorbidities with HR reduction in their multivariate logistic regression analysis. The only significant correlation of bradycardia was observed in less severe COVID-19 infection cases. (Brunetti et al., 2021).

This was similar to the result of this study as to no association between age, comorbidities and risk factors, drug history and developing bradycardia in the multivariate regression model observed. It is noteworthy that in their study, 76% of the subjects were older than 50, 53% had an underlying cardiovascular disease, and 77% had severe COVID-19 presentation. These observations suggest the absence of contraindication when administrating Remdesivir to even critical patients and those with cardiovascular diseases and risk factors despite what was generally hypothesized. (Brunetti et al., 2021). Bistrovic et al. conducted a retrospective investigation on 455 patients who received Remdesivir for the COVID-19 infection and found that the prevalence of bradycardia was significantly higher among survived patients compared to those who died (19% vs. 7%). They observed that developing bradycardia caused by Remdesivir had a significant relationship with a favorable disease course and prognosis. (Bistrovic et al., 2022). The reason may be the intensified sympathetic-adrenergic simulation in patients with severe infections and respiratory failure or that the higher concentrations of Remdesivir metabolites lead to higher simultaneous antiviral and chronotropic effects. So, developing bradycardia following Remdesivir administration should encourage clinicians to continue rather than discontinue the treatment. However, close monitoring is suggested, especially for patients with comorbidities who need synchronous medications for their underlying clinical conditions. (Bistrovic et al., 2022; Lucijanic and Bistrovic, 2022).

In the present study, almost all cases with bradycardia were asymptomatic, and for all patients, sinus bradycardia was transient and returned to normal HR after Remdesivir discontinuation. This is consistent with other case reports about Remdesivir-induced bradycardia being a transitory phenomenon. Developing bradycardia did not affect the clinical outcome of patients in the present study and did not impede the continued drug courses. Only one patient experienced presyncope symptoms at the fifth Remdesivir dose with an extreme decrease in the HR to 25bpm. The drug administration stopped, and the patient received Atropine. The HR returned to normal, and the patient could receive Remdesivir in the following days. None of the studied patients developed an arrhythmia, including atrial fibrillation and cardiac arrest. This finding may be due to the scarcity of these complications, and further investigation of these complications with larger sample sizes is required.

The sample size was small for rare cardiac complications of Remdesivir, such as atrial fibrillation, cardiac arrest, and other rarely reported cardiac arrhythmias.

Sinus bradycardia is a prevalent adverse cardiac effect of Remdesivir. It is recommended that all COVID-19 patients receiving Remdesivir, be evaluated for heart rate based on examination; and in the case of bradyarrhythmia, cardiac monitoring should be performed during administration to prevent adverse events.