The development of effective drugs for the treatment and prevention of COVID-19 has been a global priority (Beigel et al., 2020). Numerous drugs have been evaluated in clinical trials for COVID-19, for example, hydroxychloroquine, antiviral drugs, glucocorticoids, and neutralizing antibodies (Bhimraj et al., 2022; Thakur et al., 2022). However, only limited drugs have shown benefits in COVID-19 and are recommended for use by the Infectious Diseases Society of America. Since COVID-19 affects multiple organ systems and is associated with neurological and cardiovascular manifestations, several observational studies have been conducted to (Kang et al., 2020; Sharma et al., 2021) observational studies evaluated if there are mortality benefits of aspirin and angiotensin-converting enzyme inhibitors/angiotensin II receptor blockers (Srivastava and Kumar, 2021; Azad and Kumar, 2022). However, the evidence is inconclusive to recommend these therapies for COVID-19 patients.

Remdesivir is an antiviral agent with a broad spectrum of activity against several viruses that include SARS-CoV-1, SARS-CoV-2, MERS-CoV, and Filoviridae viruses (e.g., Ebola virus and Marburg virus) (Jorgensen et al., 2020; Gilead, 2022). Currently, remdesivir is approved by the Food and Drug Administration for the treatment of COVID-19 in adult and pediatric patients (Gilead, 2022). The World Health Organization, the Infectious Diseases Society of America, and the National Institute of Health recommend using remdesivir for ambulatory or hospitalized patients with mild-to-moderate COVID-19 at high risk for progression to severe disease and hospitalized patients on supplemental oxygen (Bhimraj; National Institute of Health, 2022; World Health Organization).

Generally, remdesivir is well-tolerated and the most common adverse drug reactions are nausea and transaminase elevations (Jorgensen et al., 2020). Several post-marketing studies have reported marked bradycardia with the administration of remdesivir (Attena et al., 2021; Brunetti et al., 2021; Singh and Kamath, 2021; Touafchia et al., 2021). Pharmacologically, remdesivir is a monophosphoramide nucleoside prodrug that undergoes intracellular metabolism to its active form as remdesivir triphosphate (Jorgensen et al., 2020). When activated, remdesivir is incorporated into the viral RNA by RNA-dependent RNA-polymerase, which terminates the RNA chain and inhibits viral replication. Notably, the active metabolite of remdesivir is an adenosine triphosphate analog (Nabati and Parsaee, 2022). Adenosine triphosphate has negative chronotropic and dromotropic actions by suppressing cardiac pacemakers firing at the sinoatrial node and the cardiac conduction at the atrioventricular node (Pelleg and Belhassen, 2010). Therefore, the adenosine triphosphate cardiac effects mediated by remdesivir triphosphate could play a role in the development of remdesivir-associated bradycardia.

Bradycardia can be associated with adverse health outcomes that may lead to impaired functional capacity and provocation of cardiac arrhythmias (Kusumoto et al., 2019). The reported incidence rates of bradycardia associated with remdesivir are inconclusive and vary from 16.8%–49% (Bistrovic et al., 2022; Schreiber et al., 2022). In this study, we aim to evaluate the incidence rate, severity, and potential risk factors for the development of bradycardia among hospitalized patients with COVID-19 who received remdesivir.

Remdesivir is an important therapeutic option for the treatment of certain patients with COVID-19 (Beigel et al., 2020). In the present study, we evaluated the incidence rate, the severity of bradycardia, and the potential risk factors for remdesivir-associated bradycardia in hospitalized patients with COVID-19. The incidence rate of remdesivir-associated bradycardia was 37.1% with the majority of patients (437/1,635; 26.7%) experiencing mild bradycardia. We found that age ≥65 years old, hypertension, and obesity were associated with bradycardia after remdesivir administration.

The incidence rate of remdesivir-associated bradycardia in our study was 37.1%. A study by Pantazopoulos et al. included 118 patients who received remdesivir for COVID-19 treatment and found the incidence rate to be bradycardia after remdesivir administration was 40.6% (Pantazopoulos et al., 2022). Another study by Schreiber et al. (Schreiber et al., 2022) evaluated 375 patients who experienced bradycardia after remdesivir administration for the treatment of COVID-19 and found the incidence rate to be 49%. Compared to our study, a likely explanation for the higher incidence rate of bradycardia with remdesivir in Schreiber et al. (Schreiber et al., 2022) is that they accounted for bradycardia episodes from remdesivir initiation and up to 5 days after remdesivir therapy. Notably, the half-life of remdesivir and its active metabolites is approximately 24 h (Jorgensen et al., 2020). Therefore, that study could have included more episodes of bradycardia due to COVID-19 cardiac complications (Kang et al., 2020).

Moreover, Pallotto et al. (Pallotto et al., 2021) evaluated 62 patients who received remdesivir for COVID-19 treatment and found the incidence rate of remdesivir-associated bradycardia to be 46.8%. Notably, the authors, which defined bradycardia as a heart rate <60 beats per minute in two consecutive measurements or a heart rate <50 beats per minute once which could explain the difference in the incidence rate of remdesivir-associated bradycardia compared to our study. Other studies (Attena et al., 2021; Bistrovic et al., 2022) reported lower incidence rates of bradycardia with remdesivir therapy. Attena et al. (Attena et al., 2021) included 100 patients who received remdesivir for the treatment of COVID-19 and found the incidence rate of remdesivir-associated bradycardia to be 21%. Bistrovic et al. (Bistrovic et al., 2022) evaluated 437 patients who received remdesivir for COVID-19 treatment and found the incidence rate of bradycardia after remdesivir administration was 16.8%. Variations in the incidence rates of remdesivir-associated bradycardia among these studies related to sample size, definitions of bradycardia, differences in baseline characteristics, and comorbidities profiles.

Among patients who developed bradycardia, we found that the majority of them developed mild to moderate bradycardia. Our findings are consistent with other studies that evaluated the severity of bradycardia among COVID-19 patients treated with remdesivir. The study by Attena et al. (Attena et al., 2021) found that among the 21 patients who developed bradycardia after remdesivir administration, 17 (81%) patients had mild to moderate bradycardia and only 4 (19%) patients had severe bradycardia. Also, Pantazopoulos et al. (Pantazopoulos et al., 2022) found the incidence rate of severe bradycardia associated with remdesivir was 7.5% and among those patients, one had QT interval prolongation and two patients had first-degree atrioventricular block. Our evaluation of patients with severe bradycardia revealed that the bradycardia started within 1–2 days of remdesivir initiation and resolved approximately 1 day after discontinuation of remdesivir which corresponds to the half-life of remdesivir and its active metabolites (Jorgensen et al., 2020). Our findings were consistent with the study by (Attena et al., 2021) which revealed that bradycardia is reversible once remdesivir is discontinued. Furthermore, we found that some patients with severe bradycardia may require the administration of atropine and initiation of medical emergency response.

Patients with age ≥65 years old were more likely to develop bradycardia after remdesivir administration. We also identified hypertension as a potential risk factor for remdesivir-associated bradycardia. Age-related cardiovascular changes particularly in the conduction system are plausible explanations for remdesivir-associated bradycardia in patients with age ≥65 years and those with hypertension (Strait and Lakatta, 2012). Our findings expand the results of other studies (Attena et al., 2021; Pallotto et al., 2021) that found a higher frequency of bradycardia among older adults (Attena et al., 2021; Pallotto et al., 2021) and those with hypertension (Attena et al., 2021), although these studies did not adjust for confounders. Furthermore, hypertension is associated with electrocardiographic changes that may be associated with bradycardia, yet further research is needed to explain the underlying pathophysiology (Bird et al., 2020).

Additionally, we found intensive care unit admission as a potential risk factor for remdesivir-associated bradycardia. Critical illness with SARS-CoV-2 is associated with poor outcomes and a high mortality rate because critical illness disturbs multiple organ systems including the heart function which makes patients on remdesivir therapy more vulnerable to bradycardia (Dessie and Zewotir, 2021; Gao et al., 2021). A study by Tajarernmuang et al. (Tajarernmuang et al., 2022) evaluated bradycardia and heart rate fluctuation in critically ill COVID-19 patients, and they found 71.1% (62/86) of the patient had bradycardia and those patients had longer intensive care unit length of stay.

In our study, obesity was also a potential risk factor for bradycardia after remdesivir administration (OR 1.32, 95% CI: 1.02–1.69, p = 0.03). Although obesity is a well-established risk factor for cardiovascular diseases, the underlying mechanism for bradycardia in patients with obesity after remdesivir administration is unclear. The underlying mechanism could be attributed to an imbalance between the sympathetic and parasympathetic nervous systems which leads to a higher heart rate variability in patients with obesity (Poirier et al., 2006).

Interestingly, we found that diabetes mellitus was negatively associated with bradycardia development after remdesivir administration (OR 0.71, 95% CI: 0.56–0.91, p = 0.01). The relationship between diabetes mellitus and cardiovascular diseases is a well-established and multifactorial (Grisanti, 2018). Apparently, diabetes mellitus had deleterious effects on the heart including autonomic dysfunction and cardiac remodeling. These effects may lead to higher baseline heart rates in patients with diabetes mellitus. ONTARGET/TRANSCEND clinical trials (Bohm et al., 2020) assessed the resting heart rate and the development of cardiovascular outcomes among patients with and without diabetes mellitus aged 55 years or older. The trial included 11,487 patients with diabetes mellitus and 19,450 patients without diabetes. Compared to patients without diabetes mellitus, patients with diabetes mellitus had a statistically significantly higher mean resting heart rate (71.8 ± 9.0 vs. 67.9 ± 8.8, p < 0.0001). Thus, the higher heart rate of patients with diabetes mellitus may explain why diabetes mellitus was negatively associated with bradycardia after remdesivir administration. Additional research is needed to elucidate the effects of diabetes mellitus on heart rate after remdesivir administration.

Regarding limitations, our study is observational and retrospective in nature and there is a risk of bias and incomplete or missing data. Although we evaluated the association of remdesivir with bradycardia and its potential risk factors we could not assess causality. This is particularly important because COVID-19 is associated with a wide range of cardiac complications such as arrhythmias and cardiogenic shock that may worsen health outcomes and could cause death due to direct viral cardiotoxicity and excessive inflammation (Kang et al., 2020; Abbasi, 2022). To minimize confounding and evaluate the association accurately, we evaluated bradycardia episodes from remdesivir initiation to 24 h after remdesivir therapy to account for the half-life of remdesivir and its active metabolites (Jorgensen et al., 2020). During the study period, remdesivir was not recommended for ambulatory or pediatric COVID-19 patients; thus, such patients were not included in our study. Additionally, our cohort included patients with comorbidities or concurrent drugs that could have interfered with heart rate; however, we attempted to minimize bias by adjusting for selected confounders in our multivariate logistic regression. We also adjusted for the severity of COVID-19 on admission with NEWS (Uppanisakorn et al., 2018) and baseline oxygen requirements. Lastly, we could not evaluate remdesivir-associated atrioventricular block in patients with mild-moderate bradycardia.

In conclusion, remdesivir is an important antiviral agent for the management of COVID-19. The incidence rate of remdesivir-associated bradycardia in our study was 37.1% with the majority of these patients developing only mild to moderate bradycardia which is usually a benign manifestation not needing treatment in most cases unless atrioventricular block or sick sinus syndrome are present. Age ≥65 years, hypertension, and obesity were potential risk factors for remdesivir-associated bradycardia among hospitalized COVID-19 patients. Our study informs clinicians about the characteristics of patients who are vulnerable to remdesivir-associated bradycardia and close heart rate monitoring for those patients is warranted. Future studies should evaluate the clinical outcomes of remdesivir-associated bradycardia, compare patients who received remdesivir with a cohort of patients with similar characteristics that did not receive remdesivir, and conduct the study over a long-term period.