key: cord-0756489-5dgggmv6
authors: Touafchia, Anthony; Bagheri, Haleh; Carrié, Didier; Durrieu, Geneviève; Sommet, Agnès; Montastruc, François
title: Serious bradycardia and remdesivir for coronavirus 2019 (COVID-19): a new safety concerns
date: 2021-02-27
journal: Clin Microbiol Infect
DOI: 10.1016/j.cmi.2021.02.013
sha: 398abfdb06a1741a0d6bf8fc6f1932f69d82206d
doc_id: 756489
cord_uid: 5dgggmv6

OBJECTIVES: In recent clinical trials some cardiac arrhythmias were reported with use of remdesivir for COVID-19. To address this safety concern, we investigated whether use of remdesivir for COVID-19 is associated with an increased risk of bradycardia. METHODS: Using VigiBase®, the World Health Organization Global Individual Case Safety Reports database, we compared the cases of bradycardia reported in COVID-19 patients exposed to remdesivir with those reported in COVID-19 patients exposed to hydroxychloroquine, lopinavir/ritonavir, tocilizumab or glucocorticoids. All reports of patients with COVID-19 registered up to the 23(th) of September 2020 were included. We conducted disproportionality analyses allowing the estimation of reporting odds ratios (RORs) with 95% Confident Intervals (95% CI). RESULTS: We found 302 cardiac effects including 94 bradycardia (31%) among the 2,603 reports with remdesivir prescribed in COVID-19 patients. Most of reports were serious (75, 80%) and in 16 reports (17%) evolution was fatal. Compared with hydroxychloroquine, lopinavir/ritonavir, tocilizumab or glucocorticoids, the use of remdesivir was associated with an increased risk of reporting bradycardia (ROR 1.65; 95% CI 1.23, 2.22). Consistent results were observed in other sensitivity analyses. CONCLUSIONS: This post-marketing study in a real-world setting suggests that the use of remdesivir is significantly associated with an increased risk of reporting bradycardia and serious bradycardia when compared with the use of with hydroxychloroquine, lopinavir/ritonavir, tocilizumab or glucocorticoids. This result is in line with pharmacodynamic properties of the remdesivir.

In recent clinical trials some cardiac arrhythmias were reported with use of remdesivir for COVID-19. To address this safety concern, we investigated whether use of remdesivir for COVID-19 is associated with an increased risk of bradycardia.

Using VigiBase®, the World Health Organization Global Individual Case Safety Reports database, we compared the cases of bradycardia reported in COVID-19 patients exposed to remdesivir with those reported in COVID-19 patients exposed to hydroxychloroquine, lopinavir/ritonavir, tocilizumab or glucocorticoids. All reports of patients with COVID-19 registered up to the 23 th of September 2020 were included. We conducted disproportionality analyses allowing the estimation of reporting odds ratios (RORs) with 95% Confident Intervals (95% CI).

We found 302 cardiac effects including 94 bradycardia (31%) among the 2,603 reports with remdesivir prescribed in COVID-19 patients. Most of reports were serious (75, 80%) and in

Remdesivir is a phosphoramidate prodrug. Its triphosphate form is close to adenosine triphosphate (ATP) and inhibits RNA-dependent RNA-polymerases (RdRp) from distinct Coronaviridae such as SARS-CoV-2. [1] In vitro and animal models demonstrated the antiviral activity of remdesivir. Remdesivir was authorized by Food and Drug Agency (FDA) for suspected or laboratory-confirmed COVID-19 in hospitalized adult or paediatric patients, irrespective of their severity of disease. While safety signals emerged concerning hepatic disorders, little is known about its cardiac safety. [2] In the clinical trial evaluating effects of remdesivir on ebolavirus, an arterial hypotension and cardiac arrest in one patient in the remdesivir group (among 175) was described. [3] In the first COVID-19 clinical trial, another cardiac arrest was reported in a patient exposed to remdesivir. [4] In this study, a higher proportion of patients with remdesivir treatment discontinued due to an adverse event including worsened cardiopulmonary status compared with those patients receiving placebo. In the Adaptive Covid-19 Treatment Trial (ACTT-1), more cardiac arrhythmias occurred with use of remdesivir than with placebo (8‰ versus 2‰). [5] While most trials are powered to detect benefits but not adverse events, there is an urgent need to investigate this safety concern. [6] Using VigiBase®, the World Health Organization Global Individual Case Safety Reports database, we determined whether use of remdesivir is associated with an increased risk of reporting bradycardia and serious bradycardia with in COVID-19 patients.

This pharmacovigilance study was conducted using VigiBase®. The WHO pharmacovigilance database gathers more than 23 million spontaneous reports of suspected adverse J o u r n a l P r e -p r o o f drug reactions from more than 130 countries, covering more than 90% of the world's population.

Each safety report includes information related to the reporter, the patient, the suspected and concomitant drugs, and the adverse drug reactions. The seriousness of each adverse drug reaction is also recorded. According to the official definition, a serious adverse effect is as any effects leading to death, invalidation, significant incapacity, after-effects, malformations, congenital anomalies, birth defects or requires hospitalization or prolongation of hospital stay. VigiBase® identified duplicate reports which are removed from the database. The Medical Dictionary for Regulatory Activities (MedDRA®) are used to code each adverse drug reaction. According to the clinical research French law, review from an ethics committee is not required for such observational studies. As all data from VigiBase® were deidentified, patient informed consent was not necessary.

All reports of patients with COVID-19 registered up to the 23 th of September 2020 were included. We perfumed disproportionality analysis to assess a potential increased risk of reporting bradycardia with remdesivir compared to drugs prescribed in COVID-19 patients.

Reporting Odds Ratios (ROR) with their 95% confidence interval (CI) were calculated to estimate the risk of reporting bradycardia. ROR is a ratio similar in concept to the odds ratio in case-control studies and corresponds to the exposure odds among reported cases of bradycardia over the exposure odds among reported non-cases. To test the robustness of our main analyses, four sensitivity analyses were conducted. First, to limit the potential of confounding by disease severity, we repeated the primary analysis considering only users of tocilizumab or glucocorticoids, drugs recommended in patients with severe COVID-19. Second, we restricted our analysis to only serious bradycardia. Third, we included all reports where COVID-19 drugs were defined as suspected or concomitant by reporters. Fourth, as a recent study suggested a risk of cardiac arrhythmias with hydroxychloroquine, we performed a head-to-head comparison (remdesivir versus hydroxychloroquine). [7] In addition, to address the effect of age and sex, we J o u r n a l P r e -p r o o f used stratification analyses according age groups (≤44 years, 45-64 years and ≥ 65 years) and sex.

We identified 6,574 reports with remdesivir or other drugs prescribed in COVID-19 patients. Among the 2,603 reports with remdesivir, 302 were registered as cardiac effects. Among these cardiac reports, we found 94 bradycardia reports (31%), mainly from US (88, 93%).

Patients with bradycardia had wide spectrum of age (61.2 ±18.1 years, min 6 -max 90), were mostly men (53, 56%), with a mean body weight of 93 ±28.3 kg. Mean treatment duration with remdesivir was 3.5 ±1.8 days (range 1-9). Remdesivir was the sole suspected drug in 88 patients (93%). Two-thirds of patients (61, 65%) did not received concomitant cardiovascular medications. Most of reports were serious (75, 80%) and in 16 reports (17%) evolution was fatal.

Furthermore, concurrent cardiovascular adverse effects occurred in 22 (23%) patients, mostly hypotension (10) . The median onset of bradycardia was 2.4 days (range 1-6) (data available for 18 reports). For bradycardia reports with remdesivir, reporters were mostly pharmacists (77 cases 82%) followed by physicians (11 cases, 12%) and other health professional (4 cases, 4%) (2 cases reporters were unknown).

Compared with hydroxychloroquine, lopinavir/ritonavir, tocilizumab or glucocorticoids, the use of remdesivir was associated with an increased risk of reporting bradycardia (ROR 1.65; 95% CI 1.23, 2.22) (Table) . The ROR remained significant (3.52, 95% CI 1.70-7.28) when analysis was retrited to tocilizumab or glucocorticoid users in the reference group. Consistent results were observed in other sensitivity analyses and according age groups and sex.

In this observational study including more than 6,500 reports of COVID-19 patients, we found for the first time an association between remdesivir use and reports of bradycardia. Most of bradycardia reports with remdesivir were serious and some were fatal (17%). Our study suggests an increased risk of reporting bradycardia with remdesivir compared to other drugs. While such analysis could be subject to limitations as reporting bias, our results are in line with previous reports of cardiac events in remdesivir clinical trials. [5] This safety concern allow us to recall two other cardiac safety signals with other RNA-dependent RNA-polymerase inhibitors. First, the clinical development of the antiviral BMS986094 was discontinued after a phase II study due to serious cardiac events including heart rhythm disorders. [8] Second, in 2015, FDA warned for serious bradycardia with hepatitis C treatments containing sofosbuvir. [9] Pharmacodynamic mechanism for bradycardia with remdesivir is still unknown. However, similarly to sofosbuvir, an effect on sinoatrial node function could be suggested. [10] Indeed, the active remdesivir metabolite is a nucleotide triphosphate derivative with similarity to ATP, known to slow sinoatrial node automaticity. [1] In the heart, ATP exerts a negative chronotropic and dromotropic effects. The cardiac actions of ATP are mediated by adenosine its metabolite and by a vagal reflex triggered by ATP's stimulation of vagal sensory nerve terminals in the left ventricle. [11] Although this evidence is based on data from individual case safety reports, disproportionality analyses in pharmacovigilance databases remain important and provide reproducible information essential for early post-marketing surveillance. [12, 13] This cardiac safety concerns should be particularly considered to limit the risk of cardiac adverse effects particularly in the context of polypharmacy. [14] In addition, pharmacovigilance investigations are still necessary for cardiac risk with remdesivir as a previous study reported the potential block of hERG (human ether-a-J o u r n a l P r e -p r o o f go-go gene) and prolongation of cardiac repolarization with remdesivir. [15] Post hoc analyses of trials and additional observational studies are needed to corroborate our findings. Given the increased use of remdesivir and recent FDA recommendations, physicians should be aware of this cardiac safety signal.

J o u r n a l P r e -p r o o f

All authors conceived and designed the study. FM and AT acquired the data and did the statistical analyses. All authors analyzed and interpreted the data. FM wrote the manuscript, and all authors critically revised the manuscript. FM supervised the study and is the guarantor.

All authors approved the final version of the manuscript and are accountable for its accuracy.

The work was performed during the university research time of the authors using the database which is available without fees in the department of the authors

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Finding meaningful patterns in adverse drug event reports

Risk of Adverse Drug Events Following the Virtual Addition of COVID-19 Repurposed Drugs to Drug Regimens of Frail Older Adults with Polypharmacy

Risk Assessment of Drug-Induced Long QT Syndrome for Some COVID-19 Repurposed Drugs

The authors acknowledge the Uppsala Monitoring Centre (UMC) who provided and gave permission to use the data analyzed in the present study. Access to the World Health Organization global individual case safety report database, VigiBase®, is available without fees to Dr Bagheri, Dr Durrieu and Dr. Montastruc. The authors are indebted to the National Pharmacovigilance Centers that contributed data. The opinions and conclusions in this study are not necessarily those of the various centers or of the World Health Organization.