Tixagevimab/Cilgavimab for Prevention of COVID-19 during the Omicron Surge: Retrospective Analysis of National VA Electronic Data
ScD, MA Yinong Young-Xu, MD MSc Lauren Epstein, MD Vincent C Marconi, PhD MPH Victoria Davey, BA Gabrielle Zwain, MPH Jeremy Smith, ScD Caroline Korves, PharmD Fran Cunningham, MD Robert Bonomo, MD, MPH Adit A Ginde
doi:10.1101/2022.05.28.22275716
Background: Little is known regarding the effectiveness of tixagevimab/cilgavimab in preventing SARS-CoV-2 infection in this population, particularly after the emergence of the Omicron variant. Objective: To determine the effectiveness of tixagevimab/cilgavimab for prevention of SARS-CoV-2 infection and severe disease among immunocompromised patients. Design: Retrospective cohort study with propensity matching and difference-in-difference analyses. Setting: U.S. Department of Veterans Affairs (VA) healthcare system. Participants: Veterans age ≥18 years as of January 1, 2022, receiving VA healthcare. We compared a cohort of 1,848 patients treated with at least one dose of intramuscular tixagevimab/cilgavimab to matched controls selected from 251,756 patients who were on immunocompromised or otherwise at high risk for COVID-19. Patients were followed through April 30, 2022, or until death, whichever occurred earlier. Main Outcomes: Composite of SARS-CoV-2 infection, COVID-19-related hospitalization, and allcause mortality. We used cox proportional hazards modelling to estimate the hazard ratios (HR) and 95% CI for the association between receipt of tixagevimab/cilgavimab and outcomes. Results: Most (69%) tixagevimab/cilgavimab recipients were ≥65 years old, 92% were identified as immunocompromised in electronic data, and 73% had ≥3 mRNA vaccine doses or two doses of Ad26.COV2. Compared to propensity-matched controls, tixagevimab/cilgavimab-treated patients had a lower incidence of the composite COVID-19 outcome (17/1733 [1.0%] vs 206/6354 [3.2%]; HR 0.31; 95%CI, 0.18-0.53), and individually SARS-CoV-2 infection (HR 0.34; 95%CI, 0.13-0.87), COVID-19 hospitalization (HR 0.13; 95%CI, 0.02-0.99), and all-cause mortality (HR 0.36; 95%CI, 0.18-0.73).
Limitations: Confounding by indication and immortal time bias. Conclusions: Using national real-world data from predominantly vaccinated, immunocompromised Veterans, administration of tixagevimab/cilgavimab was associated with lower rates of SARS-CoV-2 infection, COVID-19 hospitalization, and all-cause mortality during the Omicron surge.
Declaration of Authors Competing Interests VCM has received investigator-initiated research grants (to the institution) and consultation fees (both unrelated to the current work) from Eli Lilly, Bayer, Gilead Sciences and ViiV. YYX, GZ, CK, JS reported receiving grants from the US Food and Drug Administration through an interagency agreement with the Veterans Health Administration and from the US Department of Veterans Affairs Office of Rural Health.
References
Adler-Milstein, Jha, No evidence found that hospitals are using new electronic health records to increase Medicare reimbursements, Health Aff (Millwood)
Angrist, Pischke, Mastering'Metrics: The Path from Cause to Effect
Austin, Balance diagnostics for comparing the distribution of baseline covariates between treatment groups in propensity-score matched samples, Stat Med,
doi:10.1002/sim.3697Bar-On, Goldberg, Mandel, Bodenheimer, Freedman et al., Protection of BNT162b2 Vaccine Booster against Covid-19 in Israel, N Engl J Med,
doi:10.1056/NEJMoa211425Collard, Boter, Schoevers, Prevalence of frailty in community-dwelling older persons: A systematic review, J Am Geriatr Soc
Corey, Beyrer, Cohen, Michael, Bedford et al., SARS-CoV-2 Variants in Patients with Immunosuppression, N Engl J Med,
doi:10.1056/NEJMsb2104756Devoe, Gold, Mcintire, Electronic health records vs Medicaid claims: completeness of diabetes preventive care data in community health centers, Ann Fam Med
Deyo, Cherkin, Ciol, Adapting a clinical comorbidity index for use with ICD-9-CM administrative databases, J Clin Epidemiol
Dubberke, Olsen, Stwalley, Identification of Medicare Recipients at Highest Risk for Clostridium difficile Infection in the US by Population Attributable Risk Analysis, PLoS One,
doi:10.1371/journal.pone.0146822Embi, Levy, Naleway, Effectiveness of 2-Dose Vaccination with mRNA COVID-19 Vaccines Against COVID-19-Associated Hospitalizations Among Immunocompromised Adults -Nine States, January-September 2021, MMWR Morb Mortal Wkly Rep,
doi:10.15585/mmwr.mm7044e3Fried, Tangen, Walston, Frailty in older adults: Evidence for a phenotype, J Gerontol A
Hoffmann, Krüger, Schulz, Cossmann, Rocha et al., The Omicron variant is highly resistant against antibody-mediated neutralization: Implications for control of the COVID-19 pandemic, Cell,
doi:10.1016/j.cell.2021.12.032Kamar, Abravanel, Marion, Couat, Izopet et al., Three doses of an mRNA Covid-19 vaccine in solid organ transplant recipients, N Engl J Med
Kennedy, Lin, Goodhand, Infliximab is associated with attenuated immunogenicity to BNT162b2 and ChAdOx1 nCoV-19 SARS-CoV-2 vaccines in patients with IBD, Gut
Levin, Ustianowski, Wit, Launay, Avila et al., Intramuscular AZD7442 (Tixagevimab-Cilgavimab) for Prevention of Covid-19, N Engl J Med,
doi:10.1056/NEJMoa2116620.7Mazzali, Duca, Use of administrative data in healthcare research, Intern Emerg Med
Mounzer E Agha, Blake, Chilleo, Wells, Haidar, Suboptimal Response to Coronavirus Disease 2019 Messenger RNA Vaccines in Patients With Hematologic Malignancies: A Need for Vigilance in the Postmasking Era, Open Forum Infectious Diseases,
doi:.org/10.1093/ofid/ofab353Patrick, Schneeweiss, Brookhart, The implications of propensity score variable selection strategies in pharmacoepidemiology: an empirical illustration, Pharmacoepidemiology and drug safety
Petersen, Byrne, Daw, Relationship between clinical conditions and use of Veterans Affairs healthcare among Medicare-enrolled veterans, Health Serv Res
Pizer, Falsification testing of instrumental variables methods for comparative effectiveness research, Health Serv Res
Planas, Saunders, Maes, Guivel-Benhassine, Planchais et al., Considerable escape of SARS-CoV-2 Omicron to antibody neutralization, Nature,
doi:10.1038/s41586-021-04389-zPsaty, Koepsell, Lin, Assessment and control for confounding by indication in observational studies, J Am Geriatr Soc
Rogers, Kazis, Comparing the health status of VA and non-VA ambulatory patients: The Veterans' Health and Medical Outcomes Studies, J Ambul Care Manage
Takashita, Kinoshita, Yamayoshi, Sakai-Tagawa, Fujisaki et al., Efficacy of Antiviral Agents against the SARS-CoV-2 Omicron Subvariant BA.2, N Engl J Med,
doi:10.1056/NEJMc2201933Vanblargan, Errico, Halfmann, Zost, Crowe et al., An infectious SARS-CoV-2 B.1.1.529 Omicron virus escapes neutralization by therapeutic monoclonal antibodies, Nat Med,
doi:10.1038/s41591-021-01678-yYoung-Xu, Van Aalst, Mahmud, Relative Vaccine Effectiveness of High-Dose Versus Standard-Dose Influenza Vaccines Among Veterans Health Administration Patients, J Infect Dis,
doi:10.1093/infdis/jiy088.23{ 'institution': [{'name': 'medRxiv'}],
'indexed': {'date-parts': [[2022, 5, 31]], 'date-time': '2022-05-31T16:16:13Z', 'timestamp': 1654013773655},
'posted': {'date-parts': [[2022, 5, 29]]},
'group-title': 'Infectious Diseases (except HIV/AIDS)',
'reference-count': 35,
'publisher': 'Cold Spring Harbor Laboratory',
'content-domain': {'domain': [], 'crossmark-restriction': False},
'accepted': {'date-parts': [[2022, 5, 29]]},
'abstract': '<jats:title>ABSTRACT</jats:title><jats:sec><jats:title>Background</jats:title><jats:p>Little '
'is known regarding the effectiveness of tixagevimab/cilgavimab in preventing SARS-CoV-2 '
'infection in this population, particularly after the emergence of the Omicron '
'variant.</jats:p></jats:sec><jats:sec><jats:title>Objective</jats:title><jats:p>To determine '
'the effectiveness of tixagevimab/cilgavimab for prevention of SARS-CoV-2 infection and severe '
'disease among immunocompromised '
'patients.</jats:p></jats:sec><jats:sec><jats:title>Design</jats:title><jats:p>Retrospective '
'cohort study with propensity matching and difference-in-difference '
'analyses.</jats:p></jats:sec><jats:sec><jats:title>Setting</jats:title><jats:p>U.S. '
'Department of Veterans Affairs (VA) healthcare '
'system.</jats:p></jats:sec><jats:sec><jats:title>Participants</jats:title><jats:p>Veterans '
'age ≥18 years as of January 1, 2022, receiving VA healthcare. We compared a cohort of 1,848 '
'patients treated with at least one dose of intramuscular tixagevimab/cilgavimab to matched '
'controls selected from 251,756 patients who were on immunocompromised or otherwise at high '
'risk for COVID-19. Patients were followed through April 30, 2022, or until death, whichever '
'occurred earlier.</jats:p></jats:sec><jats:sec><jats:title>Main '
'Outcomes</jats:title><jats:p>Composite of SARS-CoV-2 infection, COVID-19-related '
'hospitalization, and all-cause mortality. We used cox proportional hazards modelling to '
'estimate the hazard ratios (HR) and 95% CI for the association between receipt of '
'tixagevimab/cilgavimab and '
'outcomes.</jats:p></jats:sec><jats:sec><jats:title>Results</jats:title><jats:p>Most (69%) '
'tixagevimab/cilgavimab recipients were ≥65 years old, 92% were identified as '
'immunocompromised in electronic data, and 73% had ≥3 mRNA vaccine doses or two doses of '
'Ad26.COV2. Compared to propensity-matched controls, tixagevimab/cilgavimab-treated patients '
'had a lower incidence of the composite COVID-19 outcome (17/1733 [1.0%] vs 206/6354 [3.2%]; '
'HR 0.31; 95%CI, 0.18-0.53), and individually SARS-CoV-2 infection (HR 0.34; 95%CI, '
'0.13-0.87), COVID-19 hospitalization (HR 0.13; 95%CI, 0.02-0.99), and all-cause mortality (HR '
'0.36; 95%CI, '
'0.18-0.73).</jats:p></jats:sec><jats:sec><jats:title>Limitations</jats:title><jats:p>Confounding '
'by indication and immortal time '
'bias.</jats:p></jats:sec><jats:sec><jats:title>Conclusions</jats:title><jats:p>Using national '
'real-world data from predominantly vaccinated, immunocompromised Veterans, administration of '
'tixagevimab/cilgavimab was associated with lower rates of SARS-CoV-2 infection, COVID-19 '
'hospitalization, and all-cause mortality during the Omicron surge.</jats:p></jats:sec>',
'DOI': '10.1101/2022.05.28.22275716',
'type': 'posted-content',
'created': {'date-parts': [[2022, 5, 29]], 'date-time': '2022-05-29T19:25:11Z', 'timestamp': 1653852311000},
'source': 'Crossref',
'is-referenced-by-count': 0,
'title': 'Tixagevimab/Cilgavimab for Prevention of COVID-19 during the Omicron Surge: Retrospective '
'Analysis of National VA Electronic Data',
'prefix': '10.1101',
'author': [ {'given': 'Yinong', 'family': 'Young-Xu', 'sequence': 'first', 'affiliation': []},
{'given': 'Lauren', 'family': 'Epstein', 'sequence': 'additional', 'affiliation': []},
{'given': 'Vincent C', 'family': 'Marconi', 'sequence': 'additional', 'affiliation': []},
{'given': 'Victoria', 'family': 'Davey', 'sequence': 'additional', 'affiliation': []},
{'given': 'Gabrielle', 'family': 'Zwain', 'sequence': 'additional', 'affiliation': []},
{'given': 'Jeremy', 'family': 'Smith', 'sequence': 'additional', 'affiliation': []},
{'given': 'Caroline', 'family': 'Korves', 'sequence': 'additional', 'affiliation': []},
{'given': 'Fran', 'family': 'Cunningham', 'sequence': 'additional', 'affiliation': []},
{'given': 'Robert', 'family': 'Bonomo', 'sequence': 'additional', 'affiliation': []},
{'given': 'Adit A', 'family': 'Ginde', 'sequence': 'additional', 'affiliation': []}],
'member': '246',
'reference': [ { 'key': '2022053108501042000_2022.05.28.22275716v1.1',
'doi-asserted-by': 'publisher',
'DOI': '10.1056/nejmsb2104756'},
{ 'key': '2022053108501042000_2022.05.28.22275716v1.2',
'doi-asserted-by': 'publisher',
'DOI': '10.15585/mmwr.mm7044e3'},
{ 'key': '2022053108501042000_2022.05.28.22275716v1.3',
'doi-asserted-by': 'publisher',
'DOI': '10.1056/nejmc2108861'},
{ 'key': '2022053108501042000_2022.05.28.22275716v1.4',
'doi-asserted-by': 'publisher',
'DOI': '10.1136/gutjnl-2021-324789'},
{ 'key': '2022053108501042000_2022.05.28.22275716v1.5',
'doi-asserted-by': 'publisher',
'DOI': '10.1093/ofid/ofab353'},
{ 'key': '2022053108501042000_2022.05.28.22275716v1.6',
'doi-asserted-by': 'publisher',
'DOI': '10.1056/NEJMoa2116620'},
{ 'key': '2022053108501042000_2022.05.28.22275716v1.7',
'unstructured': 'https://www.fda.gov/media/154701/download, last accessed May 9, 2022'},
{ 'key': '2022053108501042000_2022.05.28.22275716v1.8',
'doi-asserted-by': 'publisher',
'DOI': '10.1016/j.molmed.2022.04.008'},
{ 'key': '2022053108501042000_2022.05.28.22275716v1.9',
'unstructured': 'https://www.hsrd.research.va.gov/for_researchers/cdw.cfm'},
{ 'key': '2022053108501042000_2022.05.28.22275716v1.10',
'unstructured': 'https://www.hsrd.research.va.gov/for_researchers/cyber_seminars/archives/3544-notes.pdf'},
{ 'key': '2022053108501042000_2022.05.28.22275716v1.11',
'unstructured': 'https://www.pbm.va.gov/'},
{ 'key': '2022053108501042000_2022.05.28.22275716v1.12',
'unstructured': 'https://www.fda.gov/drugs/drug-safety-and-availability/fda-authorizes-revisions-evusheld-dosing'},
{ 'key': '2022053108501042000_2022.05.28.22275716v1.13',
'doi-asserted-by': 'publisher',
'DOI': '10.1111/j.1475-6773.2010.01107.x'},
{ 'key': '2022053108501042000_2022.05.28.22275716v1.14',
'doi-asserted-by': 'publisher',
'DOI': '10.1016/0895-4356(92)90133-8'},
{ 'key': '2022053108501042000_2022.05.28.22275716v1.15',
'unstructured': 'https://covid.cdc.gov/covid-data-tracker/#variant-proportions'},
{ 'issue': '2',
'key': '2022053108501042000_2022.05.28.22275716v1.16',
'doi-asserted-by': 'crossref',
'first-page': '790',
'DOI': '10.1111/1475-6773.12355',
'article-title': 'Falsification testing of instrumental variables methods for comparative '
'effectiveness research',
'volume': '51',
'year': '2016',
'journal-title': 'Health Serv Res'},
{ 'key': '2022053108501042000_2022.05.28.22275716v1.17',
'doi-asserted-by': 'publisher',
'DOI': '10.1002/pds.2098'},
{ 'key': '2022053108501042000_2022.05.28.22275716v1.18',
'doi-asserted-by': 'publisher',
'DOI': '10.1002/sim.3697'},
{ 'key': '2022053108501042000_2022.05.28.22275716v1.19',
'doi-asserted-by': 'publisher',
'DOI': '10.1093/aje/kwm324'},
{ 'key': '2022053108501042000_2022.05.28.22275716v1.20',
'doi-asserted-by': 'publisher',
'DOI': '10.1371/journal.pone.0146822'},
{ 'key': '2022053108501042000_2022.05.28.22275716v1.21',
'unstructured': 'Angrist JD , Pischke JS . Mastering’Metrics: The Path from Cause to '
'Effect. Princeton, NJ: Princeton University Press, 2014.'},
{ 'key': '2022053108501042000_2022.05.28.22275716v1.22',
'doi-asserted-by': 'publisher',
'DOI': '10.1093/infdis/jiy088'},
{ 'key': '2022053108501042000_2022.05.28.22275716v1.23',
'unstructured': 'https://www.ers.usda.gov/data-products/rural-urban-commuting-area-codes/'},
{ 'key': '2022053108501042000_2022.05.28.22275716v1.24',
'doi-asserted-by': 'publisher',
'DOI': '10.1056/NEJMOA2114255/SUPPL_FILE/NEJMOA2114255_DISCLOSURES.PDF'},
{ 'key': '2022053108501042000_2022.05.28.22275716v1.25',
'doi-asserted-by': 'publisher',
'DOI': '10.1056/NEJMc2201933'},
{ 'key': '2022053108501042000_2022.05.28.22275716v1.26',
'doi-asserted-by': 'publisher',
'DOI': '10.1038/s41586-021-04389-z'},
{ 'key': '2022053108501042000_2022.05.28.22275716v1.27',
'doi-asserted-by': 'publisher',
'DOI': '10.1016/j.cell.2021.12.032'},
{ 'key': '2022053108501042000_2022.05.28.22275716v1.28',
'doi-asserted-by': 'publisher',
'DOI': '10.1038/s41591-021-01678-y'},
{ 'key': '2022053108501042000_2022.05.28.22275716v1.29',
'doi-asserted-by': 'publisher',
'DOI': '10.1377/hlthaff.2014.0023'},
{ 'key': '2022053108501042000_2022.05.28.22275716v1.30',
'doi-asserted-by': 'publisher',
'DOI': '10.1370/afm.1279'},
{ 'key': '2022053108501042000_2022.05.28.22275716v1.31',
'doi-asserted-by': 'publisher',
'DOI': '10.1111/j.1532-5415.1999.tb01603.x'},
{ 'key': '2022053108501042000_2022.05.28.22275716v1.32',
'doi-asserted-by': 'publisher',
'DOI': '10.1111/j.1532-5415.2012.04054.x'},
{ 'key': '2022053108501042000_2022.05.28.22275716v1.33',
'doi-asserted-by': 'publisher',
'DOI': '10.1159/000048110'},
{ 'key': '2022053108501042000_2022.05.28.22275716v1.34',
'doi-asserted-by': 'publisher',
'DOI': '10.1097/00004479-200407000-00009'},
{ 'issue': '4',
'key': '2022053108501042000_2022.05.28.22275716v1.35',
'doi-asserted-by': 'crossref',
'first-page': '517',
'DOI': '10.1007/s11739-015-1213-9',
'article-title': 'Use of administrative data in healthcare research',
'volume': '10',
'year': '2015',
'journal-title': 'Intern Emerg Med'}],
'container-title': [],
'original-title': [],
'link': [ { 'URL': 'https://syndication.highwire.org/content/doi/10.1101/2022.05.28.22275716',
'content-type': 'unspecified',
'content-version': 'vor',
'intended-application': 'similarity-checking'}],
'deposited': { 'date-parts': [[2022, 5, 31]],
'date-time': '2022-05-31T15:50:35Z',
'timestamp': 1654012235000},
'score': 1,
'resource': {'primary': {'URL': 'http://medrxiv.org/lookup/doi/10.1101/2022.05.28.22275716'}},
'subtitle': [],
'short-title': [],
'issued': {'date-parts': [[2022, 5, 29]]},
'references-count': 35,
'URL': 'http://dx.doi.org/10.1101/2022.05.28.22275716',
'relation': {},
'published': {'date-parts': [[2022, 5, 29]]},
'subtype': 'preprint'}
