Cardiovascular Risks of COVID-19 Therapeutics: Integrated Analysis of FAERS, Electronic Health Records, and Transcriptomics

DOI record: { "DOI": "10.3390/ph19040574", "ISSN": [ "1424-8247" ], "URL": "http://dx.doi.org/10.3390/ph19040574", "abstract": "<jats:p>Background/Objectives: The purpose of this study was to investigate the association between cardiovascular adverse drug events (ADEs) and the use of COVID-19 medicines. Methods: The analyses were conducted by leveraging pharmacovigilance data from the Food and Drug Authority (FDA) Adverse Event Reporting System (FAERS) and TriNetX electronic health records (EHRs). Transcriptomic data from human embryonic stem cell-derived cardiomyocytes (hESC-CMs) exposed to remdesivir were analyzed to provide supportive biological context for the observed cardiovascular safety signals. Results: Comparative analysis of three approved COVID-19 therapies revealed that COVID-19 patients treated with remdesivir had a higher risk of cardiovascular events than those treated with Paxlovid or REGEN-COV. FAERS analysis further indicated that bradycardia, hypotension, and cardiac arrest were the most frequently reported cardiovascular events associated with remdesivir, which was validated by propensity score-matched EHR data. These findings suggest an association between remdesivir exposure and increased cardiovascular ADEs relative to other COVID-19 therapies. Sex-stratified analysis using FAERS and EHR did not show strong sex-dependent patterns for remdesivir-associated cardiovascular ADEs. Age-stratified analyses of EHR data showed age-associated variation across the three cardiovascular ADEs. Bradycardia displayed a non-uniform pattern with higher prevalence in the youngest and oldest age groups, hypotension showed an overall age-associated increase, and cardiac arrest showed only a weak age-associated effect. Pathway enrichment analysis on transcriptomic data revealed that the “cGMP-PKG signaling pathway”, “dilated cardiomyopathy”, and “calcium signaling pathway” were enriched among genes up-regulated by remdesivir exposure. Conclusions: In summary, our integrated analysis of pharmacovigilance, EHR, and transcriptomic data provides convergent evidence for associations between remdesivir and cardiovascular ADEs and offers biological context into these associations.</jats:p>", "alternative-id": [ "ph19040574" ], "author": [ { "affiliation": [ { "name": "Department of Pharmaceutical Sciences, College of Pharmacy, University of South Florida, Tampa, FL 33612, USA" } ], "family": "Zhu", "given": "Xinran", "sequence": "first" }, { "ORCID": "https://orcid.org/0009-0007-3438-9340", "affiliation": [ { "name": "Department of Pharmaceutical Sciences, College of Pharmacy, University of South Florida, Tampa, FL 33612, USA" } ], "authenticated-orcid": false, "family": "Kuppa", "given": "Suguna Aishwarya", "sequence": "additional" }, { "ORCID": "https://orcid.org/0000-0002-6708-884X", "affiliation": [ { "name": "Department of Pharmaceutical Sciences, College of Pharmacy, University of South Florida, Tampa, FL 33612, USA" } ], "authenticated-orcid": false, "family": "Umeukeje", "given": "Gibret", "sequence": "additional" }, { "affiliation": [ { "name": "Department of Pharmaceutical Sciences, College of Pharmacy, University of South Florida, Tampa, FL 33612, USA" } ], "family": "Morris", "given": "Robert", "sequence": "additional" }, { "affiliation": [ { "name": "Department of Mathematics & Statistics, College of Art and Science, University of South Florida, Tampa, FL 33620, USA" } ], "family": "Bui", "given": "Lan", "sequence": "additional" }, { "ORCID": "https://orcid.org/0009-0006-9526-3023", "affiliation": [ { "name": "Department of Mathematics & Statistics, College of Art and Science, University of South Florida, Tampa, FL 33620, USA" } ], "authenticated-orcid": false, "family": "Bu", "given": "Kun", "sequence": "additional" }, { "affiliation": [ { "name": "Section of Nephrology, Department of Medicine, Boston University Chobanian & Avedisian School of Medicine, Boston, MA 02118, USA" } ], "family": "Zhang", "given": "Jie", "sequence": "additional" }, { "affiliation": [ { "name": "Section of Nephrology, Department of Medicine, Boston University Chobanian & Avedisian School of Medicine, Boston, MA 02118, USA" } ], "family": "Wei", "given": "Jin", "sequence": "additional" }, { "ORCID": "https://orcid.org/0000-0003-3619-8090", "affiliation": [ { "name": "Department of Pharmaceutical Sciences, College of Pharmacy, University of South Florida, Tampa, FL 33612, USA" } ], "authenticated-orcid": false, "family": "Cheng", "given": "Feng", "sequence": "additional" } ], "container-title": "Pharmaceuticals", "container-title-short": "Pharmaceuticals", "content-domain": { "crossmark-restriction": false, "domain": [] }, "created": { "date-parts": [ [ 2026, 4, 2 ] ], "date-time": "2026-04-02T14:09:54Z", "timestamp": 1775138994000 }, "deposited": { "date-parts": [ [ 2026, 4, 2 ] ], "date-time": "2026-04-02T14:15:32Z", "timestamp": 1775139332000 }, "indexed": { "date-parts": [ [ 2026, 4, 2 ] ], "date-time": "2026-04-02T14:59:45Z", "timestamp": 1775141985565, "version": "3.50.1" }, "is-referenced-by-count": 0, "issue": "4", "issued": { "date-parts": [ [ 2026, 4, 2 ] ] }, "journal-issue": { "issue": "4", "published-online": { "date-parts": [ [ 2026, 4 ] ] } }, "language": "en", "license": [ { "URL": "https://creativecommons.org/licenses/by/4.0/", "content-version": "vor", "delay-in-days": 0, "start": { "date-parts": [ [ 2026, 4, 2 ] ], "date-time": "2026-04-02T00:00:00Z", "timestamp": 1775088000000 } } ], "link": [ { "URL": "https://www.mdpi.com/1424-8247/19/4/574/pdf", "content-type": "unspecified", "content-version": "vor", "intended-application": "similarity-checking" } ], "member": "1968", "original-title": [], "page": "574", "prefix": "10.3390", "published": { "date-parts": [ [ 2026, 4, 2 ] ] }, "published-online": { "date-parts": [ [ 2026, 4, 2 ] ] }, "publisher": "MDPI AG", "reference": [ { "DOI": "10.1186/s12879-021-06536-3", "doi-asserted-by": "crossref", "key": "ref_1", "unstructured": "Dessie, Z.G., and Zewotir, T. (2021). Mortality-related risk factors of COVID-19: A systematic review and meta-analysis of 42 studies and 423,117 patients. BMC Infect. Dis., 21." }, { "DOI": "10.1016/j.jacc.2020.08.059", "article-title": "Coronavirus and Cardiovascular Disease, Myocardial Injury, and Arrhythmia: JACC Focus Seminar", "author": "Giustino", "doi-asserted-by": "crossref", "first-page": "2011", "journal-title": "J. Am. Coll. Cardiol.", "key": "ref_2", "volume": "76", "year": "2020" }, { "DOI": "10.1128/CMR.00162-20", "article-title": "Remdesivir against COVID-19 and Other Viral Diseases", "author": "Malin", "doi-asserted-by": "crossref", "first-page": "e00162-20", "journal-title": "Clin. Microbiol. Rev.", "key": "ref_3", "volume": "34", "year": "2020" }, { "DOI": "10.1007/s40265-020-01378-w", "article-title": "Remdesivir: First Approval", "author": "Lamb", "doi-asserted-by": "crossref", "first-page": "1355", "journal-title": "Drugs", "key": "ref_4", "volume": "80", "year": "2020" }, { "DOI": "10.1056/NEJMoa2116846", "article-title": "Early Remdesivir to Prevent Progression to Severe COVID-19 in Outpatients", "author": "Gottlieb", "doi-asserted-by": "crossref", "first-page": "305", "journal-title": "N. Engl. J. Med.", "key": "ref_5", "volume": "386", "year": "2022" }, { "DOI": "10.1002/jmv.28037", "article-title": "Combination therapy with remdesivir and immunomodulators improves respiratory status in COVID-19: A retrospective study", "author": "Kojima", "doi-asserted-by": "crossref", "first-page": "5702", "journal-title": "J. Med. Virol.", "key": "ref_6", "volume": "94", "year": "2022" }, { "DOI": "10.1093/bmb/ldac037", "article-title": "Drug repurposing for COVID-19: Current evidence from randomized controlled adaptive platform trials and living systematic reviews", "author": "Augustin", "doi-asserted-by": "crossref", "first-page": "31", "journal-title": "Br. Med. Bull.", "key": "ref_7", "volume": "147", "year": "2023" }, { "DOI": "10.7861/clinmed.2022-0080", "article-title": "A practical update on the management of patients with COVID-19", "author": "Mehta", "doi-asserted-by": "crossref", "first-page": "468", "journal-title": "Clin. Med.", "key": "ref_8", "volume": "22", "year": "2022" }, { "DOI": "10.1021/acs.jmedchem.6b01594", "article-title": "Discovery and Synthesis of a Phosphoramidate Prodrug of a Pyrrolo [2,1-f][triazin-4-amino] Adenine C-Nucleoside (GS-5734) for the Treatment of Ebola and Emerging Viruses", "author": "Siegel", "doi-asserted-by": "crossref", "first-page": "1648", "journal-title": "J. Med. Chem.", "key": "ref_9", "volume": "60", "year": "2017" }, { "DOI": "10.1074/jbc.AC120.015720", "article-title": "Template-dependent inhibition of coronavirus RNA-dependent RNA polymerase by remdesivir reveals a second mechanism of action", "author": "Tchesnokov", "doi-asserted-by": "crossref", "first-page": "16156", "journal-title": "J. Biol. Chem.", "key": "ref_10", "volume": "295", "year": "2020" }, { "DOI": "10.1038/d41573-022-00047-9", "article-title": "Top companies and drugs by sales in 2021", "author": "Urquhart", "doi-asserted-by": "crossref", "first-page": "251", "journal-title": "Nat. Rev. Drug Discov.", "key": "ref_11", "volume": "21", "year": "2022" }, { "DOI": "10.1002/cpt.3337", "article-title": "Pharmacokinetics, Mass Balance, Safety, and Tolerability of Obeldesivir in Healthy Participants", "author": "Anoshchenko", "doi-asserted-by": "crossref", "first-page": "1231", "journal-title": "Clin. Pharmacol. Ther.", "key": "ref_12", "volume": "116", "year": "2024" }, { "DOI": "10.1016/S1473-3099(25)00238-5", "article-title": "Efficacy and safety of obeldesivir in low-risk, non-hospitalised patients with COVID-19 (OAKTREE): A phase 3, randomised, double-blind, placebo-controlled study", "author": "Ogbuagu", "doi-asserted-by": "crossref", "first-page": "1282", "journal-title": "Lancet Infect. Dis.", "key": "ref_13", "volume": "25", "year": "2025" }, { "DOI": "10.1128/AAC.01155-21", "article-title": "Rethinking Remdesivir: Synthesis, Antiviral Activity, and Pharmacokinetics of Oral Lipid Prodrugs", "author": "Schooley", "doi-asserted-by": "crossref", "first-page": "e0115521", "journal-title": "Antimicrob. Agents Chemother.", "key": "ref_14", "volume": "65", "year": "2021" }, { "DOI": "10.1056/NEJMoa2118542", "article-title": "Oral Nirmatrelvir for High-Risk, Nonhospitalized Adults with COVID-19", "author": "Hammond", "doi-asserted-by": "crossref", "first-page": "1397", "journal-title": "N. Engl. J. Med.", "key": "ref_15", "volume": "386", "year": "2022" }, { "DOI": "10.1126/science.abl4784", "article-title": "An oral SARS-CoV-2 M(pro) inhibitor clinical candidate for the treatment of COVID-19", "author": "Owen", "doi-asserted-by": "crossref", "first-page": "1586", "journal-title": "Science", "key": "ref_16", "volume": "374", "year": "2021" }, { "DOI": "10.1007/s40121-024-01023-z", "article-title": "Proportion of Patients in the United States Who Fill Their Nirmatrelvir/Ritonavir Prescriptions", "author": "Rudolph", "doi-asserted-by": "crossref", "first-page": "2035", "journal-title": "Infect. Dis. Ther.", "key": "ref_17", "volume": "13", "year": "2024" }, { "DOI": "10.1056/NEJMoa2108163", "article-title": "REGEN-COV Antibody Combination and Outcomes in Outpatients with Covid-19", "author": "Weinreich", "doi-asserted-by": "crossref", "first-page": "e81", "journal-title": "N. Engl. J. Med.", "key": "ref_18", "volume": "385", "year": "2021" }, { "DOI": "10.1007/s12012-021-09703-9", "article-title": "Potential Cardiotoxic Effects of Remdesivir on Cardiovascular System: A Literature Review", "author": "Nabati", "doi-asserted-by": "crossref", "first-page": "268", "journal-title": "Cardiovasc. Toxicol.", "key": "ref_19", "volume": "22", "year": "2022" }, { "DOI": "10.1056/NEJMoa2007016", "article-title": "Compassionate Use of Remdesivir for Patients with Severe COVID-19", "author": "Grein", "doi-asserted-by": "crossref", "first-page": "2327", "journal-title": "N. Engl. J. Med.", "key": "ref_20", "volume": "382", "year": "2020" }, { "article-title": "Cardiac Adverse Events With Remdesivir in COVID-19 Infection", "author": "Gupta", "first-page": "e11132", "journal-title": "Cureus", "key": "ref_21", "volume": "12", "year": "2020" }, { "DOI": "10.1161/CIRCEP.121.009811", "article-title": "Remdesivir-Induced Bradycardia in COVID-19: A Single Center Prospective Study", "author": "Attena", "doi-asserted-by": "crossref", "first-page": "e009811", "journal-title": "Circ. Arrhythm. Electrophysiol.", "key": "ref_22", "volume": "14", "year": "2021" }, { "DOI": "10.3390/ph14070611", "doi-asserted-by": "crossref", "key": "ref_23", "unstructured": "Rafaniello, C., Ferrajolo, C., Sullo, M.G., Gaio, M., Zinzi, A., Scavone, C., Gargano, F., Coscioni, E., Rossi, F., and Capuano, A. (2021). Cardiac Events Potentially Associated to Remdesivir: An Analysis from the European Spontaneous Adverse Event Reporting System. Pharmaceuticals, 14." }, { "DOI": "10.1016/j.cmi.2021.02.013", "article-title": "Serious bradycardia and remdesivir for coronavirus 2019 (COVID-19): A new safety concerns", "author": "Touafchia", "doi-asserted-by": "crossref", "first-page": "791.e5", "journal-title": "Clin. Microbiol. Infect.", "key": "ref_24", "volume": "27", "year": "2021" }, { "DOI": "10.1002/jmv.28441", "article-title": "Efficacy and safety of nirmatrelvir/ritonavir (Paxlovid) for COVID-19: A rapid review and meta-analysis", "author": "Amani", "doi-asserted-by": "crossref", "first-page": "e28441", "journal-title": "J. Med. Virol.", "key": "ref_25", "volume": "95", "year": "2023" }, { "DOI": "10.3346/jkms.2023.38.e347", "article-title": "Effectiveness and Adverse Events of Nirmatrelvir/Ritonavir Versus Molnupiravir for COVID-19 in Outpatient Setting: Multicenter Prospective Observational Study", "author": "Park", "doi-asserted-by": "crossref", "first-page": "e347", "journal-title": "J. Korean Med. Sci.", "key": "ref_26", "volume": "38", "year": "2023" }, { "DOI": "10.2174/0113816128280987240214103432", "article-title": "Safety Profile of Paxlovid in the Treatment of COVID-19", "author": "Lv", "doi-asserted-by": "crossref", "first-page": "666", "journal-title": "Curr. Pharm. Des.", "key": "ref_27", "volume": "30", "year": "2024" }, { "DOI": "10.1002/ohn.278", "article-title": "Postmarketing Reporting of Paxlovid-Related Dysgeusia: A Real-World Pharmacovigilance Study", "author": "Cvancara", "doi-asserted-by": "crossref", "first-page": "55", "journal-title": "Otolaryngol. Head Neck Surg.", "key": "ref_28", "volume": "169", "year": "2023" }, { "DOI": "10.1080/14740338.2025.2471509", "article-title": "Effects of nirmatrelvir/ritonavir (Paxlovid) on the nervous system: Analysis on adverse events released by FDA", "author": "Gao", "doi-asserted-by": "crossref", "first-page": "669", "journal-title": "Expert Opin. Drug Saf.", "key": "ref_29", "volume": "25", "year": "2026" }, { "DOI": "10.1053/j.ajkd.2025.02.603", "article-title": "Safety and Effectiveness of Nirmatrelvir-Ritonavir in Patients With Advanced Kidney Dysfunction and COVID-19", "author": "Anand", "doi-asserted-by": "crossref", "first-page": "202", "journal-title": "Am. J. Kidney Dis.", "key": "ref_30", "volume": "86", "year": "2025" }, { "DOI": "10.15420/ecr.2024.04", "article-title": "Cardiovascular Drug Interactions with Nirmatrelvir/Ritonavir for COVID-19: Considerations for Daily Practice", "author": "Ferri", "doi-asserted-by": "crossref", "first-page": "e15", "journal-title": "Eur. Cardiol.", "key": "ref_31", "volume": "19", "year": "2024" }, { "article-title": "Paxlovid-Induced Symptomatic Bradycardia and Syncope", "author": "Ganipisetti", "first-page": "e33831", "journal-title": "Cureus", "key": "ref_32", "volume": "15", "year": "2023" }, { "DOI": "10.3390/ph15121472", "doi-asserted-by": "crossref", "key": "ref_33", "unstructured": "Zou, J., and Jing, F. (2022). Cardiovascular Adverse Events Associated with Monoclonal Antibody Products in Patients with COVID-19. Pharmaceuticals, 15." }, { "article-title": "Acute Hypersensitivity Reaction After Casirivimab/Imdevimab Infusion in a COVID-19-Positive Young Male: Myopericarditis or Kounis Syndrome?", "author": "Rivera", "first-page": "e31125", "journal-title": "Cureus", "key": "ref_34", "volume": "14", "year": "2022" }, { "DOI": "10.1177/0018578718795271", "article-title": "The Newly Available FAERS Public Dashboard: Implications for Health Care Professionals", "author": "Kumar", "doi-asserted-by": "crossref", "first-page": "75", "journal-title": "Hosp. Pharm.", "key": "ref_35", "volume": "54", "year": "2019" }, { "DOI": "10.1002/advs.202203388", "article-title": "Investigating and Resolving Cardiotoxicity Induced by COVID-19 Treatments using Human Pluripotent Stem Cell-Derived Cardiomyocytes and Engineered Heart Tissues", "author": "Xu", "doi-asserted-by": "crossref", "first-page": "e2203388", "journal-title": "Adv. Sci.", "key": "ref_36", "volume": "9", "year": "2022" }, { "DOI": "10.3390/antibiotics10121477", "doi-asserted-by": "crossref", "key": "ref_37", "unstructured": "Poliseno, M., Gallo, C., Cibelli, D.C., Minafra, G.A., Bottalico, I.F., Bruno, S.R., D’Errico, M.L., Montemurro, L., Rizzo, M., and Barbera, L. (2021). Efficacy and Safety of Remdesivir over Two Waves of the SARS-CoV-2 Pandemic. Antibiotics, 10." }, { "DOI": "10.1016/j.antiviral.2020.104955", "article-title": "Antiviral activity and safety of remdesivir against SARS-CoV-2 infection in human pluripotent stem cell-derived cardiomyocytes", "author": "Choi", "doi-asserted-by": "crossref", "first-page": "104955", "journal-title": "Antivir. Res.", "key": "ref_38", "volume": "184", "year": "2020" }, { "DOI": "10.1016/j.amjcard.2020.04.054", "article-title": "Cardiovascular Safety of Potential Drugs for the Treatment of Coronavirus Disease 2019", "author": "Aggarwal", "doi-asserted-by": "crossref", "first-page": "147", "journal-title": "Am. J. Cardiol.", "key": "ref_39", "volume": "128", "year": "2020" }, { "DOI": "10.3389/jpps.2023.11208", "doi-asserted-by": "crossref", "key": "ref_40", "unstructured": "Kingsley, R., Rohlman, C., Otto, A., Chaudhary, R., Phelan, D., and Kirchoff, R. (2023). Remdesivir-induced conduction abnormalities: A molecular model-based explanation. J. Pharm. Pharm. Sci., 26." }, { "DOI": "10.1016/j.jacc.2022.08.800", "article-title": "Cardiovascular Drug Interactions With Nirmatrelvir/Ritonavir in Patients With COVID-19: JACC Review Topic of the Week", "author": "Abraham", "doi-asserted-by": "crossref", "first-page": "1912", "journal-title": "J. Am. Coll. Cardiol.", "key": "ref_41", "volume": "80", "year": "2022" }, { "DOI": "10.1002/jps.22109", "article-title": "Review of the basic and clinical pharmacology of sulfobutylether-beta-cyclodextrin (SBECD)", "author": "Luke", "doi-asserted-by": "crossref", "first-page": "3291", "journal-title": "J. Pharm. Sci.", "key": "ref_42", "volume": "99", "year": "2010" }, { "DOI": "10.1136/heartjnl-2021-319971", "article-title": "Non-invasive markers for sudden cardiac death risk stratification in dilated cardiomyopathy", "author": "Pooranachandran", "doi-asserted-by": "crossref", "first-page": "998", "journal-title": "Heart", "key": "ref_43", "volume": "108", "year": "2022" }, { "DOI": "10.3389/fphar.2020.00072", "doi-asserted-by": "crossref", "key": "ref_44", "unstructured": "Kistamás, K., Veress, R., Horváth, B., Bányász, T., Nánási, P.P., and Eisner, D.A. (2020). Calcium Handling Defects and Cardiac Arrhythmia Syndromes. Front. Pharmacol., 11." }, { "DOI": "10.1001/jama.2023.12945", "article-title": "Monoclonal Antibody and Oral Antiviral Treatment of SARS-CoV-2 Infection in US Nursing Homes", "author": "McGarry", "doi-asserted-by": "crossref", "first-page": "561", "journal-title": "JAMA", "key": "ref_45", "volume": "330", "year": "2023" }, { "DOI": "10.1016/j.chembiol.2024.03.008", "article-title": "SARS-CoV-2 resistance to monoclonal antibodies and small-molecule drugs", "author": "Iketani", "doi-asserted-by": "crossref", "first-page": "632", "journal-title": "Cell Chem. Biol.", "key": "ref_46", "volume": "31", "year": "2024" }, { "DOI": "10.1016/j.jval.2021.04.1270", "article-title": "PIN82 Real-World Utilization of Remdesivir in 2020: A Retrospective Cohort Study", "author": "Mozaffari", "doi-asserted-by": "crossref", "first-page": "S121", "journal-title": "Value Health", "key": "ref_47", "volume": "24", "year": "2021" } ], "reference-count": 47, "references-count": 47, "relation": {}, "resource": { "primary": { "URL": "https://www.mdpi.com/1424-8247/19/4/574" } }, "score": 1, "short-title": [], "source": "Crossref", "subject": [], "subtitle": [], "title": "Cardiovascular Risks of COVID-19 Therapeutics: Integrated Analysis of FAERS, Electronic Health Records, and Transcriptomics", "type": "journal-article", "update-policy": "https://doi.org/10.3390/mdpi_crossmark_policy", "volume": "19" }