Identification of Bradycardia Following Remdesivir Administration Through the US Food and Drug Administration American College of Medical Toxicology COVID-19 Toxic Pharmacovigilance Project

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 i...

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Autores principales: Devgun, Jason M., Zhang, Rongmei, Brent, Jeffrey, Wax, Paul, Burkhart, Keith, Meyn, Alison, Campleman, Sharan, Abston, Stephanie, Aldy, Kim
Formato: Online Artículo Texto
Lenguaje:English
Publicado: American Medical Association 2023
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9929701/
https://www.ncbi.nlm.nih.gov/pubmed/36787141
http://dx.doi.org/10.1001/jamanetworkopen.2022.55815
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author Devgun, Jason M.
Zhang, Rongmei
Brent, Jeffrey
Wax, Paul
Burkhart, Keith
Meyn, Alison
Campleman, Sharan
Abston, Stephanie
Aldy, Kim
author_facet Devgun, Jason M.
Zhang, Rongmei
Brent, Jeffrey
Wax, Paul
Burkhart, Keith
Meyn, Alison
Campleman, Sharan
Abston, Stephanie
Aldy, Kim
author_sort Devgun, Jason M.
collection PubMed
description 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.
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spelling pubmed-99297012023-02-16 Identification of Bradycardia Following Remdesivir Administration Through the US Food and Drug Administration American College of Medical Toxicology COVID-19 Toxic Pharmacovigilance Project Devgun, Jason M. Zhang, Rongmei Brent, Jeffrey Wax, Paul Burkhart, Keith Meyn, Alison Campleman, Sharan Abston, Stephanie Aldy, Kim JAMA Netw Open Original Investigation 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. American Medical Association 2023-02-14 /pmc/articles/PMC9929701/ /pubmed/36787141 http://dx.doi.org/10.1001/jamanetworkopen.2022.55815 Text en Copyright 2023 Devgun JM et al. JAMA Network Open. https://creativecommons.org/licenses/by/4.0/This is an open access article distributed under the terms of the CC-BY License.
spellingShingle Original Investigation
Devgun, Jason M.
Zhang, Rongmei
Brent, Jeffrey
Wax, Paul
Burkhart, Keith
Meyn, Alison
Campleman, Sharan
Abston, Stephanie
Aldy, Kim
Identification of Bradycardia Following Remdesivir Administration Through the US Food and Drug Administration American College of Medical Toxicology COVID-19 Toxic Pharmacovigilance Project
title Identification of Bradycardia Following Remdesivir Administration Through the US Food and Drug Administration American College of Medical Toxicology COVID-19 Toxic Pharmacovigilance Project
title_full Identification of Bradycardia Following Remdesivir Administration Through the US Food and Drug Administration American College of Medical Toxicology COVID-19 Toxic Pharmacovigilance Project
title_fullStr Identification of Bradycardia Following Remdesivir Administration Through the US Food and Drug Administration American College of Medical Toxicology COVID-19 Toxic Pharmacovigilance Project
title_full_unstemmed Identification of Bradycardia Following Remdesivir Administration Through the US Food and Drug Administration American College of Medical Toxicology COVID-19 Toxic Pharmacovigilance Project
title_short Identification of Bradycardia Following Remdesivir Administration Through the US Food and Drug Administration American College of Medical Toxicology COVID-19 Toxic Pharmacovigilance Project
title_sort identification of bradycardia following remdesivir administration through the us food and drug administration american college of medical toxicology covid-19 toxic pharmacovigilance project
topic Original Investigation
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9929701/
https://www.ncbi.nlm.nih.gov/pubmed/36787141
http://dx.doi.org/10.1001/jamanetworkopen.2022.55815
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