Is the 90-day incidence of arterial thromboembolism and venous thromboembolism higher in patients hospitalized with COVID-19 vs in patients hospitalized with influenza?
In this retrospective cohort study that included 93 906 patients, hospitalization with COVID-19 before vaccine availability and during vaccine availability was significantly associated with higher 90-day risk of venous thromboembolism (adjusted hazard ratios, 1.60 and 1.89, respectively) vs hospitalization with influenza in 2018-2019, but there was no significant difference in the risk of arterial thromboembolism among those hospitalized with COVID-19 during either period (adjusted hazard ratios, 1.04 and 1.07) vs those hospitalized with influenza.
Hospitalization with COVID-19 both before and during vaccine availability was significantly associated with a higher risk of venous thromboembolism, but not arterial thromboembolism, vs hospitalization with influenza in 2018-2019.
The incidence of arterial thromboembolism and venous thromboembolism in persons with COVID-19 remains unclear.
To measure the 90-day risk of arterial thromboembolism and venous thromboembolism in patients hospitalized with COVID-19 before or during COVID-19 vaccine availability vs patients hospitalized with influenza.
Design, Setting, and Participants
Retrospective cohort study of 41 443 patients hospitalized with COVID-19 before vaccine availability (April-November 2020), 44 194 patients hospitalized with COVID-19 during vaccine availability (December 2020-May 2021), and 8269 patients hospitalized with influenza (October 2018-April 2019) in the US Food and Drug Administration Sentinel System (data from 2 national health insurers and 4 regional integrated health systems).
COVID-19 or influenza (identified by hospital diagnosis or nucleic acid test).
Main Outcomes and Measures
Hospital diagnosis of arterial thromboembolism (acute myocardial infarction or ischemic stroke) and venous thromboembolism (deep vein thrombosis or pulmonary embolism) within 90 days. Outcomes were ascertained through July 2019 for patients with influenza and through August 2021 for patients with COVID-19. Propensity scores with fine stratification were developed to account for differences between the influenza and COVID-19 cohorts. Weighted Cox regression was used to estimate the adjusted hazard ratios (HRs) for outcomes during each COVID-19 vaccine availability period vs the influenza period.
A total of 85 637 patients with COVID-19 (mean age, 72 [SD, 13.0] years; 50.5% were male) and 8269 with influenza (mean age, 72 [SD, 13.3] years; 45.0% were male) were included. The 90-day absolute risk of arterial thromboembolism was 14.4% (95% CI, 13.6%-15.2%) in patients with influenza vs 15.8% (95% CI, 15.5%-16.2%) in patients with COVID-19 before vaccine availability (risk difference, 1.4% [95% CI, 1.0%-2.3%]) and 16.3% (95% CI, 16.0%-16.6%) in patients with COVID-19 during vaccine availability (risk difference, 1.9% [95% CI, 1.1%-2.7%]). Compared with patients with influenza, the risk of arterial thromboembolism was not significantly higher among patients with COVID-19 before vaccine availability (adjusted HR, 1.04 [95% CI, 0.97-1.11]) or during vaccine availability (adjusted HR, 1.07 [95% CI, 1.00-1.14]). The 90-day absolute risk of venous thromboembolism was 5.3% (95% CI, 4.9%-5.8%) in patients with influenza vs 9.5% (95% CI, 9.2%-9.7%) in patients with COVID-19 before vaccine availability (risk difference, 4.1% [95% CI, 3.6%-4.7%]) and 10.9% (95% CI, 10.6%-11.1%) in patients with COVID-19 during vaccine availability (risk difference, 5.5% [95% CI, 5.0%-6.1%]). Compared with patients with influenza, the risk of venous thromboembolism was significantly higher among patients with COVID-19 before vaccine availability (adjusted HR, 1.60 [95% CI, 1.43-1.79]) and during vaccine availability (adjusted HR, 1.89 [95% CI, 1.68-2.12]).
Conclusions and Relevance
Based on data from a US public health surveillance system, hospitalization with COVID-19 before and during vaccine availability, vs hospitalization with influenza in 2018-2019, was significantly associated with a higher risk of venous thromboembolism within 90 days, but there was no significant difference in the risk of arterial thromboembolism within 90 days.
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CME Disclosure Statement: Unless noted, all individuals in control of content reported no relevant financial relationships. If applicable, all relevant financial relationships have been mitigated.
Corresponding Author: Vincent Lo Re III, MD, MSCE, Perelman School of Medicine, University of Pennsylvania, 423 Guardian Dr, 836 Blockley Hall, Philadelphia, PA 19104 (email@example.com).
Accepted for Publication: July 12, 2022.
Author Contributions: Drs Lo Re and Cocoros had full access to all of the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis.
Concept and design: Lo Re, Dutcher, Connolly, Perez-Vilar, Carbonari, Hennessy, Kuntz, McMahill-Walraven, Pawloski, Cocoros.
Acquisition, analysis, or interpretation of data: Lo Re, Connolly, Perez-Vilar, Carbonari, DeFor, Djibo, Harrington, Hou, Hennessy, Hubbard, Kempner, Kuntz, McMahill-Walraven, Mosley, Pawloski, Petrone, Pishko, Driscoll, Steiner, Zhou, Cocoros.
Drafting of the manuscript: Lo Re, Carbonari, Djibo.
Critical revision of the manuscript for important intellectual content: All authors.
Statistical analysis: Connolly, Hou, Hubbard, McMahill-Walraven, Zhou.
Obtained funding: Lo Re, Driscoll.
Administrative, technical, or material support: Lo Re, Dutcher, Carbonari, DeFor, Djibo, Harrington, Kempner, Kuntz, McMahill-Walraven, Mosley, Pawloski, Petrone, Driscoll, Cocoros.
Supervision: Lo Re, Perez-Vilar, Harrington, McMahill-Walraven, Driscoll, Cocoros.
Conflict of Interest Disclosures: Dr Lo Re reported receving personal fees from Takeda. Dr Dutcher reported being an employee of the US Food and Drug Administration (FDA). Dr Harrington reported receiving grants from the Kaiser Permanente Garfield Memorial Fund for COVID-19–related research. Dr Hennessy reported receiving grants from Pfizer and Johnson & Johnson; receiving personal fees from Novo Nordisk, Arbor Pharmaceuticals, the Medullary Thyroid Cancer Consortium (Novo Nordisk, AstraZeneca, GlaxoSmithKline, and Eli Lilly), Biogen, Intercept Pharmaceuticals, Provention Bio, bluebird bio, and Amylyx Pharmaceuticals; and being a special government employee of the FDA. Dr Hubbard reported receiving grants from Merck, Pfizer, and Johnson & Johnson. Dr McMahill-Walraven reported being an employee of CVS Health Clinical Trial Services LLC, an affiliate of CVS Health, and being responsible for activities with the FDA Sentinel System, the BEST program, and other distributed research networks (including the Academy of Managed Care Pharmacy’s Biologics and Biosimilars Collective Intelligence Collaborative; the Reagan-Udall’s Foundation IMEDS multisite research service agreements funded by Abbvie, Merck, Novartis, and Pfizer; the Patient-Centered Outcomes Research Institute; Research Action for Health Network; TherapeuticsMD; and the National Evaluation System for Health Technology Coordinating Center), and for multisite research subcontracts funded by the FDA, the National Institutes of Health, Pfizer, Janssen, and GlaxoSmithKline that use Sentinel System infrastructure to analyze health claims data administered by Aetna, also a CVS Health affiliate. Dr Pishko reported receiving research funding from Sanofi Genzyme Research. Ms Zhou reported being an employee of Humana. No other disclosures were reported.
Funding/Support: This work was supported by contract 75F40119D10037 (task order 75F40119F19001) with the US Food and Drug Administration (FDA).
Role of the Funder/Sponsor: Employees of the FDA contributed as coauthors to the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication. The FDA had the opportunity to review the final manuscript but did not have the right to either prevent publication or direct it to a specific journal.
Disclaimer: The views expressed reflect those of the authors and should not be construed to represent the FDA’s policies or views.
Additional Contributions: We thank the following individuals who each received financial support for their contributions to this work: Brian Kit, MD, MPH (clinical subject matter expert), at the FDA; Catherine Cleveland, BA (research data integration architect), Daniel Vaughn, MS (database architect), and Celeste Machen (project manager), and all 3 are at Kaiser Permanente Northwest Center for Health Research; Ron Johnson, MA (data reporting and analytics consultant), Vina Graham, BS (programmer analyst), and Monica Fujii, MPH (project manager), and all 3 are at Kaiser Permanente Washington Health Research Institute; Thomas Harkins, MPH, MA (project director), and Vinit Nair, BPharm, MS, RhP (principal investigator), and both are at Humana Healthcare Research Inc; Anne Marie Kline, MS, CHES (data manager) at CVS Health Clinical Trial Services (Aetna); Mahesh Maiyani, MBA (data specialist), and Karen Glenn, BS (programmer), and both are at Kaiser Permanente Colorado Institute for Health Research; Jacob Zillhardt, MS (senior research informatics programmer analyst), Dianne Eggen, MPH, BSN (research nurse), and Laurie VanArman, LPN (research nurse), and all 3 are at HealthPartners Institute; and Jenice Ko, BS (research assistant), at Harvard Pilgrim Health Care Institute. We also thank the following individuals who did not receive financial support for their contributions to this work: John Weeks, MBA (senior research data warehouse engineer), Roy Pardee, JD, MA (principal engineer), and Yonah Karp, BA, MFA (manager of data projects and programs), and all 3 are at Kaiser Permanente Washington Health Research Institute; and Laura Shockro, BA (project manager), Tawil Contreras, BS (research analyst), Suzanne Carter, MA, PhD, AB (research analyst), Daniel Kiernan, BS (research analyst), and Candace Fuller, PhD, MPH (research scientist), and all 5 are at Harvard Pilgrim Health Care Institute. We thank the following organizations that provided data or support for this work: Aetna, a CVS Health company; Harvard Pilgrim Health Care Institute; HealthPartners Institute; Humana Healthcare Research Inc; Kaiser Permanente Colorado Institute for Health Research; Kaiser Permanente Northwest Center for Health Research; and Kaiser Permanente Washington Health Research Institute.
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