. 2022 Feb;15(2):501-513.

doi: 10.1111/cts.13168. Epub 2021 Oct 31.

Cardiovascular events and safety outcomes associated with remdesivir using a World Health Organization international pharmacovigilance database

Se Yong Jung¹, Min Seo Kim^{2

3}, Han Li⁴, Keum Hwa Lee⁵, Ai Koyanagi^{6

7

8}, Marco Solmi^{9

10

11}, Andreas Kronbichler¹², Elena Dragioti¹³, Kalthoum Tizaoui¹⁴, Sarah Cargnin¹⁵, Salvatore Terrazzino¹⁵, Sung Hwi Hong¹⁶, Ramy Abou Ghayda¹⁷, Nam Kyun Kim^{18

19}, Seo Kyoung Chung²⁰, Louis Jacob^{6

21}, Joe-Elie Salem²², Dong Keon Yon²³, Seung Won Lee²⁴, Karel Kostev²⁵, Ah Young Kim¹, Jo Won Jung¹, Jae Young Choi¹, Jin Soo Shin²⁶, Soon-Jung Park²⁷, Seong Woo Choi²⁸, Kiwon Ban²⁹, Sung-Hwan Moon²⁷, Yun Young Go³⁰, Jae Il Shin⁵, Lee Smith³¹

Affiliations

¹ Division of Pediatric Cardiology, Department of Pediatrics, Yonsei University College of Medicine, Seoul, Korea.
² College of Medicine, Korea University, Seoul, Korea.
³ Samsung Advanced Institute for Health Sciences and Technology (SAIHST), Samsung Medical Center, Sungkyunkwan University, Seoul, Korea.
⁴ University of Florida College of Medicine, Gainesville, Florida, USA.
⁵ Department of Pediatrics, Yonsei University College of Medicine, Seoul, Korea.
⁶ Research and Development Unit, Parc Sanitari Sant Joan de Déu, Universitat de Barcelona, Fundació Sant Joan de Déu, CIBERSAM, Barcelona, Spain.
⁷ ICREA, Barcelona, Spain.
⁸ Instituto de Salud Carlos III, Centro de Investigación Biomédica en Red de Salud Mental, CIBERSAM, Madrid, Spain.
⁹ Department of Psychiatry, University of Ottawa, Ottawa, Ontario, Canada.
¹⁰ Department of Mental Health, The Ottawa Hospital, Ottawa, Ontario, Canada.
¹¹ Ottawa Hospital Research Institute (OHRI) Clinical Epidemiology Program, University of Ottawa, Ottawa, Ontario, Canada.
¹² Department of Internal Medicine IV, Medical University Innsbruck, Innsbruck, Austria.
¹³ Department of Health, Medicine and Caring Sciences, Pain and Rehabilitation Centre, Linköping University, Linköping, Sweden.
¹⁴ Laboratory Microorganismes and Active Biomolecules, Sciences Faculty of Tunis, Tunis El Manar University, Tunis, Tunisia.
¹⁵ Department of Pharmaceutical Sciences, Interdepartmental Research Center of Pharmacogenetics and Pharmacogenomics (CRIFF), University of Piemonte Orientale, Novara, Italy.
¹⁶ Yonsei University College of Medicine, Seoul, Korea.
¹⁷ Urology Institute, University Hospitals and Case Western Reserve University, Cleveland, Ohio, USA.
¹⁸ Department of Pediatrics, Emory University, Atlanta, Georgia, USA.
¹⁹ Division of Cardiovascular Surgery, Department of Thoracic and Cardiovascular Surgery, Yonsei University College of Medicine, Seoul, Korea.
²⁰ College of Medicine, Ewha Womans University, Seoul, Korea.
²¹ Faculty of Medicine, University of Versailles Saint-Quentin-en-Yvelines, Montigny-le-Bretonneux, France.
²² Department of Pharmacology, INSERM, CIC-1901 Paris-Est, CLIP Galilée, UNICO-GRECO Cardio-oncology Program, Pitié-Salpêtrière Hospital, Assistance Publique-Hôpitaux de Paris, Sorbonne Université, Paris, France.
²³ Department of Pediatrics, Seoul National University Children's Hospital, Seoul National University College of Medicine, Seoul, Korea.
²⁴ Department of Data Science, Sejong University College of Software Convergence, Seoul, Korea.
²⁵ University Clinic of Marburg, Marburg, Germany.
²⁶ Infectious Disease Research Center, Korea Research Institute of Chemical Technology, Daejeon, Korea.
²⁷ Stem Cell Research Institute, T&R Biofab Co. Ltd, Siheung, Korea.
²⁸ Department of Physiology, Ischemic/Hypoxic Disease Institute, Seoul National University College of Medicine, Seoul, Korea.
²⁹ Department of Biomedical Sciences, City University of Hong Kong, Hong Kong SAR, China.
³⁰ Department of Infectious Diseases and Public Health, City University of Hong Kong, Hong Kong SAR, China.
³¹ The Cambridge Centre for Sport and Exercise Sciences, Anglia Ruskin University, Cambridge, UK.

PMID: 34719115
PMCID: PMC8841455
DOI: 10.1111/cts.13168

Cardiovascular events and safety outcomes associated with remdesivir using a World Health Organization international pharmacovigilance database

Se Yong Jung et al. Clin Transl Sci. 2022 Feb.

. 2022 Feb;15(2):501-513.

doi: 10.1111/cts.13168. Epub 2021 Oct 31.

Authors

Affiliations

¹ Division of Pediatric Cardiology, Department of Pediatrics, Yonsei University College of Medicine, Seoul, Korea.
² College of Medicine, Korea University, Seoul, Korea.
³ Samsung Advanced Institute for Health Sciences and Technology (SAIHST), Samsung Medical Center, Sungkyunkwan University, Seoul, Korea.
⁴ University of Florida College of Medicine, Gainesville, Florida, USA.
⁵ Department of Pediatrics, Yonsei University College of Medicine, Seoul, Korea.
⁶ Research and Development Unit, Parc Sanitari Sant Joan de Déu, Universitat de Barcelona, Fundació Sant Joan de Déu, CIBERSAM, Barcelona, Spain.
⁷ ICREA, Barcelona, Spain.
⁸ Instituto de Salud Carlos III, Centro de Investigación Biomédica en Red de Salud Mental, CIBERSAM, Madrid, Spain.
⁹ Department of Psychiatry, University of Ottawa, Ottawa, Ontario, Canada.
¹⁰ Department of Mental Health, The Ottawa Hospital, Ottawa, Ontario, Canada.
¹¹ Ottawa Hospital Research Institute (OHRI) Clinical Epidemiology Program, University of Ottawa, Ottawa, Ontario, Canada.
¹² Department of Internal Medicine IV, Medical University Innsbruck, Innsbruck, Austria.
¹³ Department of Health, Medicine and Caring Sciences, Pain and Rehabilitation Centre, Linköping University, Linköping, Sweden.
¹⁴ Laboratory Microorganismes and Active Biomolecules, Sciences Faculty of Tunis, Tunis El Manar University, Tunis, Tunisia.
¹⁵ Department of Pharmaceutical Sciences, Interdepartmental Research Center of Pharmacogenetics and Pharmacogenomics (CRIFF), University of Piemonte Orientale, Novara, Italy.
¹⁶ Yonsei University College of Medicine, Seoul, Korea.
¹⁷ Urology Institute, University Hospitals and Case Western Reserve University, Cleveland, Ohio, USA.
¹⁸ Department of Pediatrics, Emory University, Atlanta, Georgia, USA.
¹⁹ Division of Cardiovascular Surgery, Department of Thoracic and Cardiovascular Surgery, Yonsei University College of Medicine, Seoul, Korea.
²⁰ College of Medicine, Ewha Womans University, Seoul, Korea.
²¹ Faculty of Medicine, University of Versailles Saint-Quentin-en-Yvelines, Montigny-le-Bretonneux, France.
²² Department of Pharmacology, INSERM, CIC-1901 Paris-Est, CLIP Galilée, UNICO-GRECO Cardio-oncology Program, Pitié-Salpêtrière Hospital, Assistance Publique-Hôpitaux de Paris, Sorbonne Université, Paris, France.
²³ Department of Pediatrics, Seoul National University Children's Hospital, Seoul National University College of Medicine, Seoul, Korea.
²⁴ Department of Data Science, Sejong University College of Software Convergence, Seoul, Korea.
²⁵ University Clinic of Marburg, Marburg, Germany.
²⁶ Infectious Disease Research Center, Korea Research Institute of Chemical Technology, Daejeon, Korea.
²⁷ Stem Cell Research Institute, T&R Biofab Co. Ltd, Siheung, Korea.
²⁸ Department of Physiology, Ischemic/Hypoxic Disease Institute, Seoul National University College of Medicine, Seoul, Korea.
²⁹ Department of Biomedical Sciences, City University of Hong Kong, Hong Kong SAR, China.
³⁰ Department of Infectious Diseases and Public Health, City University of Hong Kong, Hong Kong SAR, China.
³¹ The Cambridge Centre for Sport and Exercise Sciences, Anglia Ruskin University, Cambridge, UK.

PMID: 34719115
PMCID: PMC8841455
DOI: 10.1111/cts.13168

Abstract

On October 2020, the US Food and Drug Administration (FDA) approved remdesivir as the first drug for the treatment of coronavirus disease 2019 (COVID-19), increasing remdesivir prescriptions worldwide. However, potential cardiovascular (CV) toxicities associated with remdesivir remain unknown. We aimed to characterize the CV adverse drug reactions (ADRs) associated with remdesivir using VigiBase, an individual case safety report database of the World Health Organization (WHO). Disproportionality analyses of CV-ADRs associated with remdesivir were performed using reported odds ratios and information components. We conducted in vitro experiments using cardiomyocytes derived from human pluripotent stem cell cardiomyocytes (hPSC-CMs) to confirm cardiotoxicity of remdesivir. To distinguish drug-induced CV-ADRs from COVID-19 effects, we restricted analyses to patients with COVID-19 and found that, after adjusting for multiple confounders, cardiac arrest (adjusted odds ratio [aOR]: 1.88, 95% confidence interval [CI]: 1.08-3.29), bradycardia (aOR: 2.09, 95% CI: 1.24-3.53), and hypotension (aOR: 1.67, 95% CI: 1.03-2.73) were associated with remdesivir. In vitro data demonstrated that remdesivir reduced the cell viability of hPSC-CMs in time- and dose-dependent manners. Physicians should be aware of potential CV consequences following remdesivir use and implement adequate CV monitoring to maintain a tolerable safety margin.

Trial registration: ClinicalTrials.gov NCT04314817.

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Conflict of interest statement

All authors have no conflict of interest.

Figures

**FIGURE 1**
Overlap between cardiovascular entities. AMI, acute myocardial infarction

**FIGURE 2**
Redemsivir elicits cardiotoxic effects in hPSC‐CMs (a) and hiPSC‐CMs (b). Cardiotoxicity analyses was performed using hPSC‐CMs (hESC‐CMs and hiPSC‐CMs cell lines) in the presence of various concentrations of remdesivir. After 24 and 48 h post‐treatment, cell viability was determined by using the CellTiter 96 AQueous One Solution Cell Proliferation Assay (MTS, Promega). The data represent the mean (±SD) of at least two independent experiments performed in triplicate. CC₅₀, 50% cytotoxic concentration; hESC‐CMs, cardiomyocyte derived from human embryonic stem cells; hiPSC‐CMs, cardiomyocytes derived from human embryonic stem cells

See this image and copyright information in PMC

References

1. Kim JS, Lee JY, Yang JW, et al. Immunopathogenesis and treatment of cytokine storm in COVID‐19. Theranostics. 2021;11:316‐329. - PMC - PubMed
1. Helmy YA, Fawzy M, Elaswad A, Sobieh A, Kenney SP, Shehata AA. The COVID‐19 pandemic: a comprehensive review of taxonomy, genetics, epidemiology, diagnosis, treatment, and control. J Clin Med. 2020;9:1225. - PMC - PubMed
1. Brown AJ, Won JJ, Graham RL, et al. Broad spectrum antiviral remdesivir inhibits human endemic and zoonotic deltacoronaviruses with a highly divergent RNA dependent RNA polymerase. Antiviral Res. 2019;169:104541. - PMC - PubMed
1. Wang M, Cao R, Zhang L, et al. Remdesivir and chloroquine effectively inhibit the recently emerged novel coronavirus (2019‐nCoV) in vitro. Cell Res. 2020;30:269‐271. - PMC - PubMed
1. Han YJ, Lww KH, Yoon S, et al. Treatment of severe acute respiratory syndrome (SARS), Middle East respiratory syndrome (MERS), and coronavirus disease 2019 (COVID‐19): a systematic review of in vitro, in vivo, and clinical trials. Theranostics. 2021;11:1207‐1231. - PMC - PubMed

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Cardiovascular events and safety outcomes associated with remdesivir using a World Health Organization international pharmacovigilance database

Affiliations

Cardiovascular events and safety outcomes associated with remdesivir using a World Health Organization international pharmacovigilance database

Authors

Affiliations

Abstract

Conflict of interest statement

Figures

References

Publication types

MeSH terms

Substances

Associated data

Grants and funding

LinkOut - more resources

Full Text Sources

Medical