Identification of Bradycardia Following Remdesivir Administration Through the US Food and Drug Administration American College of Medical Toxicology COVID-19 Toxic Pharmacovigilance Project
Authors: Devgun Jason M. , Zhang Rongmei , Brent Jeffrey , Wax Paul , Burkhart Keith , Meyn Alison , Campleman Sharan , Abston Stephanie , Aldy Kim ,   Toxicology Investigators Consortium FACT Study Group, Amirshahi Maryann , Boyle Katherine , Buchanan Jennie , Carey Jennifer , Heard Kennon , Hendrickson Robert , Kazzi Ziad , Lavonas Eric , Levine Michael , Olives Travis , Pizon Anthony , Schimmel Jonathan , Sharma Kapil , Spyres Meghan , Wiegand Timothy 
Published: February 2023

Importance

The rapid spread and mortality associated with COVID-19 emphasized a need for surveillance system development to identify adverse events (AEs) to emerging therapeutics. Bradycardia is a remdesivir infusion–associated AE listed in the US Food and Drug Administration–approved prescribing information.

Objective

To evaluate the magnitude and duration of bradycardic events following remdesivir administration.

Design, Setting, and Participants

A multicenter cohort study of patients with recorded heart rate less than 60 beats per minute within 24 hours after administration of a remdesivir dose was conducted between November 23, 2020, and October 31, 2021. Participants included patients hospitalized with COVID-19 at 15 medical centers across the US. Patients excluded had AEs unrelated to bradycardia, AEs in addition to bradycardia, or first onset of bradycardia after 5 remdesivir doses.

Exposures

Remdesivir administration.

Main Outcomes and Measures

Linear mixed-effect models for the minimum HR before starting remdesivir and within 24 hours of each dose included doses as fixed effects. Baseline covariates were age (≥65 years vs &amp;lt;65 years), sex (male vs female), cardiovascular disease history (yes vs no), and concomitant use of bradycardia-associated medications. The interactions between variables and doses were considered fixed-effects covariates to adjust models.

Results

A total of 188 patients were included in the primary analysis and 181 in the secondary analysis. The cohort included 108 men (57.4%); 75 individuals (39.9%) were non-Hispanic White and mean (SD) age was 61.3 (15.4) years. Minimum HR after doses 1 to 5 was lower than before remdesivir. Mean minimum HR was lowest after dose 4, decreasing by −15.2 beats per minute (95% CI, −17.4 to −13.1; P &amp;lt; .001) compared with before remdesivir administration. Mean (SD) minimum HR was 55.6 (10.2) beats per minute across all 5 doses. Of 181 patients included in time-to-event analysis, 91 had their first episode of bradycardia within 23.4 hours (95% CI, 20.1-31.5 hours) and 91 had their lowest HR within 60.7 hours (95% CI, 54.0-68.3 hours). Median time to first bradycardia after starting remdesivir was shorter for patients aged 65 years or older vs those younger than 65 years (18.7 hours; 95% CI, 16.8-23.7 hours vs 31.5 hours; 95% CI, 22.7-39.3 hours; P = .04). Median time to lowest HR was shorter for men vs women (54.2 hours; 95% CI, 47.3-62.0 hours vs 71.0 hours; 95% CI, 59.5-79.6 hours; P = .02).

Conclusions and Relevance

In this cohort study, bradycardia occurred during remdesivir infusion and persisted. Given the widespread use of remdesivir, practitioners should be aware of this safety signal.