TY - JOUR
T1 - Identification of Bradycardia Following Remdesivir Administration Through the US Food and Drug Administration American College of Medical Toxicology COVID-19 Toxic Pharmacovigilance Project
AU - Toxicology Investigators Consortium FACT Study Group
AU - Devgun, Jason M.
AU - Zhang, Rongmei
AU - Brent, Jeffrey
AU - Wax, Paul
AU - Burkhart, Keith
AU - Meyn, Alison
AU - Campleman, Sharan
AU - Abston, Stephanie
AU - Aldy, Kim
N1 - Publisher Copyright:
© 2023 American Medical Association. All rights reserved.
PY - 2023/2
Y1 - 2023/2
N2 - 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 <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 < .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.
AB - 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 <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 < .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.
UR - http://www.scopus.com/inward/record.url?scp=85148092530&partnerID=8YFLogxK
U2 - 10.1001/jamanetworkopen.2022.55815
DO - 10.1001/jamanetworkopen.2022.55815
M3 - Article
C2 - 36787141
AN - SCOPUS:85148092530
SN - 2574-3805
VL - 6
JO - JAMA Network Open
JF - JAMA Network Open
IS - 2
M1 - e2255815
ER -